@article{belardinelli_li_martin_zeiler_lian_avanzi_wiersma_nguyen_angala_moura_et al._2022, title={2-Aminoimidazoles Inhibit Mycobacterium abscessus Biofilms in a Zinc-Dependent Manner}, volume={23}, ISSN={["1422-0067"]}, DOI={10.3390/ijms23062950}, abstractNote={Biofilm growth is thought to be a significant obstacle to the successful treatment of Mycobacterium abscessus infections. A search for agents capable of inhibiting M. abscessus biofilms led to our interest in 2-aminoimidazoles and related scaffolds, which have proven to display antibiofilm properties against a number of Gram-negative and Gram-positive bacteria, including Mycobacterium tuberculosis and Mycobacterium smegmatis. The screening of a library of 30 compounds led to the identification of a compound, AB-2-29, which inhibits the formation of M. abscessus biofilms with an IC50 (the concentration required to inhibit 50% of biofilm formation) in the range of 12.5 to 25 μM. Interestingly, AB-2-29 appears to chelate zinc, and its antibiofilm activity is potentiated by the addition of zinc to the culture medium. Preliminary mechanistic studies indicate that AB-2-29 acts through a distinct mechanism from those reported to date for 2-aminoimidazole compounds.}, number={6}, journal={INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES}, author={Belardinelli, Juan M. and Li, Wei and Martin, Kevin H. and Zeiler, Michael J. and Lian, Elena and Avanzi, Charlotte and Wiersma, Crystal J. and Nguyen, Tuan Vu and Angala, Bhanupriya and Moura, Vinicius C. N. and et al.}, year={2022}, month={Mar} }
 @article{borrel_melander_fourches_2021, title={Cheminformatics Analysis of Fluoroquinolones and Their Inhibition Potency Against Four Pathogens}, volume={40}, ISSN={["1868-1751"]}, DOI={10.1002/minf.202000215}, abstractNote={Abstract}, number={5}, journal={MOLECULAR INFORMATICS}, author={Borrel, Alexandre and Melander, Christian and Fourches, Denis}, year={2021}, month={May} }
 @article{jeon_ackart_li_jackson_melander_melander_abramovitch_chicco_basaraba_obregon-henao_2019, title={2-aminoimidazoles collapse mycobacterial proton motive force and block the electron transport chain}, volume={9}, ISSN={["2045-2322"]}, DOI={10.1038/s41598-018-38064-7}, abstractNote={Abstract}, journal={SCIENTIFIC REPORTS}, author={Jeon, Albert Byungyun and Ackart, David F. and Li, Wei and Jackson, Mary and Melander, Roberta J. and Melander, Christian and Abramovitch, Robert B. and Chicco, Adam J. and Basaraba, Randall J. and Obregon-Henao, Andres}, year={2019}, month={Feb} }
 @article{nguyen_minrovic_melander_melander_2019, title={Identification of Anti-Mycobacterial Biofilm Agents Based on the 2-Aminoimidazole Scaffold}, volume={14}, ISSN={["1860-7187"]}, DOI={10.1002/cmdc.201900033}, abstractNote={Abstract}, number={9}, journal={CHEMMEDCHEM}, author={Nguyen, T. Vu and Minrovic, Bradley M. and Melander, Roberta J. and Melander, Christian}, year={2019}, month={May}, pages={927–937} }
 @article{martin_melander_brackett_scott_chandler_nguyen_minrovic_harrill_ernst_manoil_et al._2019, title={Small Molecule Potentiation of Gram-Positive Selective Antibiotics against Acinetobacter baumannii}, volume={5}, ISSN={["2373-8227"]}, DOI={10.1021/acsinfecdis.9b00067}, abstractNote={In 2016, the World Health Organization deemed antibiotic resistance one of the biggest threats to global health, food security, and development. The need for new methods to combat infections caused by antibiotic resistant pathogens will require a variety of approaches to identifying effective new therapeutic strategies. One approach is the identification of small molecule adjuvants that potentiate the activity of antibiotics of demonstrated utility, whose efficacy is abated by resistance, both acquired and intrinsic. To this end, we have identified compounds that enhance the efficacy of antibiotics normally ineffective against Gram-negative pathogens because of the outer membrane permeability barrier. We identified two adjuvant compounds that dramatically enhance sensitivity of Acinetobacter baumannii to macrolide and glycopeptide antibiotics, with reductions in minimum inhibitory concentrations as high as 256-fold, and we observed activity across a variety of clinical isolates. Mode of action studies indicate that these adjuvants likely work by modulating lipopolysaccharide synthesis or assembly. The adjuvants were active in vivo in a Galleria mellonella infection model, indicating potential for use in mammalian infections.}, number={7}, journal={ACS INFECTIOUS DISEASES}, author={Martin, Sara E. and Melander, Roberta J. and Brackett, Christopher M. and Scott, Alison J. and Chandler, Courtney E. and Nguyen, Catherine M. and Minrovic, Bradley M. and Harrill, Sarah E. and Ernst, Robert K. and Manoil, Colin and et al.}, year={2019}, month={Jul}, pages={1223–1230} }
 @article{nguyen_peszko_melander_melander_2019, title={Using 2-aminobenzimidazole derivatives to inhibit Mycobacterium smegmatis biofilm formation}, volume={10}, ISSN={["2040-2511"]}, DOI={10.1039/c9md00025a}, abstractNote={Biofilm formation by mycobacteria can lead to enhanced antibiotic tolerance.}, number={3}, journal={MEDCHEMCOMM}, author={Nguyen, T. Vu and Peszko, Matthew T. and Melander, Roberta J. and Melander, Christian}, year={2019}, month={Mar}, pages={456–459} }
 @article{hubble_hubbard_minrovic_melander_melander_2019, title={Using Small-Molecule Adjuvants to Repurpose Azithromycin for Use against Pseudomonas aeruginosa}, volume={5}, ISSN={["2373-8227"]}, DOI={10.1021/acsinfecdis.8b00288}, abstractNote={A major contributor to fatalities in cystic fibrosis (CF) patients stems from infection with opportunistic bacterium Pseudomonas aeruginosa. As a result of the CF patient's vulnerability to bacterial infections, one of the main treatment focuses is antibiotic therapy. However, the highly adaptive nature of P. aeruginosa, in addition to the intrinsic resistance to many antibiotics exhibited by most Gram-negative bacteria, means that multi-drug-resistant (MDR) strains are increasingly prevalent. This makes the eradication of pseudomonal lung infections nearly impossible once the infection becomes chronic. New methods to treat pseudomonal infections are greatly needed in order to eradicate MDR bacteria found within the respiratory tract, and ultimately better the quality of life for CF patients. Herein, we describe a novel approach to combatting pseudomonal infections through the use of bis-2-aminoimidazole adjuvants that can potentiate the activity of a macrolide antibiotic commonly prescribed to CF patients as an anti-inflammatory agent. Our lead bis-2-AI exhibits a 1024-fold reduction in the minimum inhibitory concentration of azithromycin in vitro and displays activity in a Galleria mellonella model of infection.}, number={1}, journal={ACS INFECTIOUS DISEASES}, author={Hubble, Veronica B. and Hubbard, Brittany A. and Minrovic, Bradley M. and Melander, Roberta J. and Melander, Christian}, year={2019}, month={Jan}, pages={141–151} }
 @misc{melander_zurawski_melander_2018, title={Narrow-spectrum antibacterial agents}, volume={9}, ISSN={["2040-2511"]}, DOI={10.1039/c7md00528h}, abstractNote={Narrow-spectrum antibiotics have the potential to limit selection for and spread of resistance, and to elicit a lesser detrimental effect upon the host microbiome.}, number={1}, journal={MEDCHEMCOMM}, author={Melander, Roberta J. and Zurawski, Daniel V. and Melander, Christian}, year={2018}, month={Jan}, pages={12–21} }
 @article{milton_minrovic_harris_kang_jung_lewis_thompson_melander_zeng_melander_et al._2018, title={Re-sensitizing Multidrug Resistant Bacteria to Antibiotics by Targeting Bacterial Response Regulators: Characterization and Comparison of Interactions between 2-Aminoimidazoles and the Response Regulators BfmR from Acinetobacter baumannii and QseB from Francisella spp.}, volume={5}, ISSN={["2296-889X"]}, DOI={10.3389/fmolb.2018.00015}, abstractNote={2-aminoimidazole (2-AI) compounds inhibit the formation of bacterial biofilms, disperse preformed biofilms, and re-sensitize multidrug resistant bacteria to antibiotics. 2-AIs have previously been shown to interact with bacterial response regulators, but the mechanism of interaction is still unknown. Response regulators are one part of two-component systems (TCS). TCSs allow cells to respond to changes in their environment, and are used to trigger quorum sensing, virulence factors, and antibiotic resistance. Drugs that target the TCS signaling process can inhibit pathogenic behavior, making this a potent new therapeutic approach that has not yet been fully exploited. We previously laid the groundwork for the interaction of the Acinetobacter baumannii response regulator BfmR with an early 2-AI derivative. Here, we further investigate the response regulator/2-AI interaction and look at a wider library of 2-AI compounds. By combining molecular modeling with biochemical and cellular studies, we expand on a potential mechanism for interaction between response regulators and 2-AIs. We also establish that Francisella tularensis/novicida, encoding for only three known response regulators, can be a model system to study the interaction between 2-AIs and response regulators. We show that knowledge gained from studying Francisella can be applied to the more complex A. baumannii system, which contains over 50 response regulators. Understanding the impact of 2-AIs on response regulators and their mechanism of interaction will lead to the development of more potent compounds that will serve as adjuvant therapies to broad-range antibiotics.}, journal={FRONTIERS IN MOLECULAR BIOSCIENCES}, author={Milton, Morgan E. and Minrovic, Bradley M. and Harris, Danni L. and Kang, Brian and Jung, David and Lewis, Caleb P. and Thompson, Richele J. and Melander, Roberta J. and Zeng, Daina and Melander, Christian and et al.}, year={2018}, month={Feb} }
 @article{jeon_obregon-henao_ackart_podell_belardinelli_jackson_nguyen_blackledge_melander_melander_et al._2017, title={2-aminoimidazoles potentiate beta-lactam antimicrobial activity against Mycobacterium tuberculosis by reducing beta-lactamase secretion and increasing cell envelope permeability}, volume={12}, number={7}, journal={PLoS One}, author={Jeon, A. B. and Obregon-Henao, A. and Ackart, D. F. and Podell, B. K. and Belardinelli, J. M. and Jackson, M. and Nguyen, T. V. and Blackledge, M. S. and Melander, R. J. and Melander, C. and et al.}, year={2017} }
 @article{yuen_walper_melde_daniele_stenger_2017, title={Electrolyte-sensing transistor decals enabled by ultrathin microbial nanocellulose}, volume={7}, journal={Scientific Reports}, author={Yuen, J. D. and Walper, S. A. and Melde, B. J. and Daniele, M. A. and Stenger, D. A.}, year={2017} }
 @article{draughn_allen_routh_stone_kirker_boegli_schuchman_linder_baynes_james_et al._2017, title={Evaluation of a 2-aminoimidazole variant as adjuvant treatment for dermal bacterial infections}, volume={11}, journal={Drug Design Development and Therapy}, author={Draughn, G. L. and Allen, C. L. and Routh, P. A. and Stone, M. R. and Kirker, K. R. and Boegli, A. and Schuchman, R. M. and Linder, K. E. and Baynes, R. E. and James, G. and et al.}, year={2017}, pages={153–162} }
 @article{byrne-nash_lucero_osbaugh_melander_melander_feldheim_2017, title={Probing the Mechanism of LAL-32, a Gold Nanoparticle-Based Antibiotic Discovered through Small Molecule Variable Ligand Display}, volume={28}, ISSN={["1043-1802"]}, DOI={10.1021/acs.bioconjchem.7b00199}, abstractNote={The unrelenting rise of antimicrobial-resistant bacteria has necessitated the search for novel antibiotic solutions. Herein we describe further mechanistic studies on a 2.0-nm-diameter gold nanoparticle-based antibiotic (designated LAL-32). This antibiotic exhibits bactericidal activity against the Gram-negative bacterium Escherichia coli at 1.0 μM, a concentration significantly lower than several clinically available antibiotics (such as ampicillin and gentamicin), and acute treatment with LAL-32 does not give rise to spontaneous resistant mutants. LAL-32 treatment inhibits cellular division, daughter cell separation, and twin-arginine translocation (Tat) pathway dependent shuttling of proteins to the periplasm. Furthermore, we have found that the cedA gene imparts increased resistance to LAL-32, and shown that an E. coli cedA transposon mutant exhibits increased susceptibility to LAL-32. Taken together, these studies further implicate cell division pathways as the target for this nanoparticle-based antibiotic and demonstrate that there may be inherently higher barriers for resistance evolution against nanoscale antibiotics in comparison to their small molecule counterparts.}, number={7}, journal={BIOCONJUGATE CHEMISTRY}, author={Byrne-Nash, Rose and Lucero, Danielle M. and Osbaugh, Niki A. and Melander, Roberta J. and Melander, Christian and Feldheim, Daniel L.}, year={2017}, month={Jul}, pages={1807–1810} }
 @article{barker_martin_chandler_nguyen_harris_goodell_melander_doi_ernst_melander_2017, title={Small molecule adjuvants that suppress both chromosomal and mcr-1 encoded colistin-resistance and amplify colistin efficacy in polymyxin-susceptible bacteria}, volume={25}, ISSN={["1464-3391"]}, DOI={10.1016/j.bmc.2017.08.055}, abstractNote={Bacterial resistance to polymyxin antibiotics has taken on a new and more menacing form. Common are genomically-encoded resistance mechanisms to polymyxins, specifically colistin (polymyxin E), however, the plasmid-borne mobile colistin resistance-1 (mcr-1) gene has recently been identified and poses a new threat to global public health. Within six months of initial identification in Chinese swine in November 2015, the first human clinical isolation in the US was reported (Apr. 2016). Herein we report successful reversion of mcr-1-driven colistin resistance in Acinetobacter baumannii, Klebsiella pneumoniae, and Escherichia coli with adjuvants we previously reported as modulators of chromosomally-encoded colistin resistance. Further screening of our in-house library of nitrogen-dense heterocycles has identified additional chemical scaffolds that actively attenuate colistin resistance. Ultimately, we present a diverse cohort of adjuvants that both sensitize colistin-resistant and colistin-susceptible bacteria to this antibiotic, thus providing a potential avenue to both reduce colistin dosage and toxicity, and overcome colistin resistance.}, number={20}, journal={BIOORGANIC & MEDICINAL CHEMISTRY}, author={Barker, William T. and Martin, Sara E. and Chandler, Courtney E. and Nguyen, T. Vu. and Harris, Tyler L. and Goodell, Christopher and Melander, Roberta J. and Doi, Yohei and Ernst, Robert K. and Melander, Christian}, year={2017}, month={Oct}, pages={5749–5753} }
 @article{milton_allen_feldmann_bobay_jung_stephens_melander_theisen_zeng_thompson_et al._2017, title={Structure of the Francisella response regulator QseB receiver domain, and characterization of QseB inhibition by antibiofilm 2-aminoimidazole-based compounds}, volume={106}, ISSN={["1365-2958"]}, DOI={10.1111/mmi.13759}, abstractNote={Summary}, number={2}, journal={MOLECULAR MICROBIOLOGY}, author={Milton, Morgan E. and Allen, C. Leigh and Feldmann, Erik A. and Bobay, Benjamin G. and Jung, David K. and Stephens, Matthew D. and Melander, Roberta J. and Theisen, Kelly E. and Zeng, Daina and Thompson, Richele J. and et al.}, year={2017}, month={Oct}, pages={223–235} }
 @article{garcia_blackledge_michalek_su_ptacek_eipers_morrow_lefkowitz_melander_wu_2017, title={Targeting of Streptococcus mutans Biofilms by a Novel Small Molecule Prevents Dental Caries and Preserves the Oral Microbiome}, volume={96}, ISSN={["1544-0591"]}, DOI={10.1177/0022034517698096}, abstractNote={Dental caries is a costly and prevalent disease characterized by the demineralization of the tooth’s enamel. Disease outcome is influenced by host factors, dietary intake, cariogenic bacteria, and other microbes. The cariogenic bacterial species Streptococcus mutans metabolizes sucrose to initiate biofilm formation on the tooth surface and consequently produces lactic acid to degrade the tooth’s enamel. Persistence of S. mutans biofilms in the oral cavity can lead to tooth decay. To date, no anticaries therapies that specifically target S. mutans biofilms but do not disturb the overall oral microbiome are available. We screened a library of 2-aminoimidazole antibiofilm compounds with a biofilm dispersion assay and identified a small molecule that specifically targets S. mutans biofilms. At 5 µM, the small molecule annotated 3F1 dispersed 50% of the established S. mutans biofilm but did not disperse biofilms formed by the commensal species Streptococcus sanguinis or Streptococcus gordonii. 3F1 dispersed S. mutans biofilms independently of biofilm-related factors such as antigen I/II and glucosyltransferases. 3F1 treatment effectively prevented dental caries by controlling S. mutans in a rat caries model without perturbing the oral microbiota. Our study demonstrates that selective targeting of S. mutans biofilms by 3F1 was able to effectively reduce dental caries in vivo without affecting the overall oral microbiota shaped by the intake of dietary sugars, suggesting that the pathogenic biofilm-specific treatment is a viable strategy for disease prevention.}, number={7}, journal={JOURNAL OF DENTAL RESEARCH}, author={Garcia, S. S. and Blackledge, M. S. and Michalek, S. and Su, L. and Ptacek, T. and Eipers, P. and Morrow, C. and Lefkowitz, E. J. and Melander, C. and Wu, H.}, year={2017}, month={Jul}, pages={807–814} }
 @article{melander_melander_2017, title={The Challenge of Overcoming Antibiotic Resistance: An Adjuvant Approach?}, volume={3}, ISSN={["2373-8227"]}, DOI={10.1021/acsinfecdis.7b00071}, abstractNote={Antibiotic resistance is one of the greatest current threats to human health, and without significant action we face the chilling prospect of a world without effective antibiotics. Although continued effort toward the development of new antibiotics, particularly those with novel mechanisms of action, remains crucial, this alone probably will not be enough to prevail, and it is imperative that additional approaches are also explored. One such approach is the identification of adjuvants that augment the activity of current antibiotics. This approach has the potential to render an antibiotic against which bacteria have developed resistance once again effective, to broaden the spectrum of an antibiotic, and to lower the required dose of an antibiotic. In this viewpoint we discuss some of the advantages and disadvantages of the use of adjuvants, and describe various approaches to their identification.}, number={8}, journal={ACS INFECTIOUS DISEASES}, author={Melander, Roberta J. and Melander, Christian}, year={2017}, month={Aug}, pages={559–563} }
 @article{nguyen_blackledge_lindsey_minrovic_ackart_jeon_obregon-henao_melander_basaraba_melander_2017, title={The Discovery of 2-Aminobenzimidazoles That Sensitize Mycobacterium smegmatis and M. tuberculosis to beta-Lactam Antibiotics in a Pattern Distinct from beta-Lactamase Inhibitors}, volume={56}, ISSN={["1521-3773"]}, DOI={10.1002/anie.201612006}, abstractNote={Abstract}, number={14}, journal={ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}, author={Nguyen, T. Vu and Blackledge, Meghan S. and Lindsey, Erick A. and Minrovic, Bradley M. and Ackart, David F. and Jeon, Albert B. and Obregon-Henao, Andres and Melander, Roberta J. and Basaraba, Randall J. and Melander, Christian}, year={2017}, month={Mar}, pages={3940–3944} }
 @article{stephens_yodsanit_melander_2016, title={Evaluation of ethyl N-(2-phenethyl) carbamate analogues as biofilm inhibitors of methicillin resistant Staphylococcus aureus}, volume={14}, ISSN={["1477-0539"]}, DOI={10.1039/c6ob00706f}, abstractNote={A small molecule library consisting of 45 compounds was synthesized based on the bacterial metabolite ethylN-(2-phenethyl) carbamate. From this library, a more potent, broad-spectrum inhibitor of MRSA biofilm formation was discovered.}, number={28}, journal={ORGANIC & BIOMOLECULAR CHEMISTRY}, author={Stephens, Matthew D. and Yodsanit, Nisakorn and Melander, Christian}, year={2016}, pages={6853–6856} }
 @article{melander_liu_stephens_bewley_melander_2016, title={Marine sponge alkaloids as a source of anti-bacterial adjuvants}, volume={26}, ISSN={["1464-3405"]}, DOI={10.1016/j.bmcl.2016.11.018}, abstractNote={Novel approaches that do not rely upon developing microbicidal compounds are sorely needed to combat multidrug resistant (MDR) bacteria. The potential of marine secondary metabolites to serve as a source of non-traditional anti-bacterial agents is demonstrated by showing that pyrrole-imidazole alkaloids inhibit biofilm formation and suppress antibiotic resistance.}, number={24}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Melander, Roberta J. and Liu, Hong-bing and Stephens, Matthew D. and Bewley, Carole A. and Melander, Christian}, year={2016}, month={Dec}, pages={5863–5866} }
 @article{stephens_hubble_ernst_hoek_melander_cavanagh_melander_2016, title={Potentiation of Francisella resistance to conventional antibiotics through small molecule adjuvants}, volume={7}, ISSN={["2040-2511"]}, DOI={10.1039/c5md00353a}, abstractNote={A screen of 20 compounds identified small molecule adjuvants capable of potentiating antibiotic activity against Francisella philomiragia.}, number={1}, journal={MEDCHEMCOMM}, author={Stephens, Matthew D. and Hubble, Veroncia B. and Ernst, Robert K. and Hoek, Monique L. and Melander, Roberta J. and Cavanagh, John and Melander, Christian}, year={2016}, pages={128–131} }
 @article{stephens_yodsanit_melander_2016, title={Potentiation of the fosmidomycin analogue FR 900098 with substituted 2-oxazolines against Francisella novicida}, volume={7}, ISSN={["2040-2511"]}, DOI={10.1039/c6md00365f}, abstractNote={A library of 33 compounds was screened for potentiation of the antibiotic FR 900098 against the Francisella tularensis surrogate Francisella novicida.}, number={10}, journal={MEDCHEMCOMM}, author={Stephens, Matthew D. and Yodsanit, Nisakorn and Melander, Christian}, year={2016}, pages={1952–1956} }
 @article{brackett_furlani_anderson_krishnamurthy_melander_moskowitz_ernst_melander_2016, title={Second generation modifiers of colistin resistance show enhanced activity and lower inherent toxicity}, volume={72}, ISSN={["0040-4020"]}, DOI={10.1016/j.tet.2015.09.019}, abstractNote={We recently reported a 2-aminoimidazole-based antibiotic adjuvant that reverses colistin resistance in two species of Gram-negative bacteria. Mechanistic studies in Acinetobacter baumannii demonstrated that this compound downregulated the PmrAB two-component system and abolished a lipid A modification that is required for colistin resistance. We now report the synthesis and evaluation of two separate libraries of substituted 2-aminoimidazole analogues based on this parent compound. From these libraries, a new small molecule was identified that lowers the minimum inhibitory concentration of colistin by up to 32-fold greater than the parent compound while also displaying less inherent bacterial effect, thereby minimizing the likelihood of resistance evolution.}, number={25}, journal={TETRAHEDRON}, author={Brackett, Christopher M. and Furlani, Robert E. and Anderson, Ryan G. and Krishnamurthy, Aparna and Melander, Roberta J. and Moskowitz, Samuel M. and Ernst, Robert K. and Melander, Christian}, year={2016}, month={Jun}, pages={3549–3553} }
 @article{pan_fan_wu_melander_liu_2015, title={A new small molecule inhibits Streptococcus mutans biofilms invitro and in vivo}, volume={119}, DOI={10.1111/jam.12940}, abstractNote={The aim of this study was to identify new small molecules that can inhibit Streptococcus mutans biofilms by in vitro and in vivo model.}, number={5}, journal={Journal of Applied Microbiology}, author={Pan, W. and Fan, M. and Wu, H. and Melander, C. and Liu, C.}, year={2015}, pages={1403–1411} }
 @article{wahome_beauchesne_pedone_cavanagh_melander_zimba_moeller_2015, title={Augmenting anti-cancer natural products with a small molecule adjuvant}, volume={13}, number={1}, journal={Marine Drugs}, author={Wahome, P. G. and Beauchesne, K. R. and Pedone, A. C. and Cavanagh, J. and Melander, C. and Zimba, P. and Moeller, P. D. R.}, year={2015}, pages={65–75} }
 @article{melander_melander_2015, title={From Worms to Targeting Virulence Factors}, volume={22}, ISSN={["1879-1301"]}, DOI={10.1016/j.chembiol.2015.04.005}, abstractNote={Rising antibiotic resistance means that alternative antibacterial strategies are sorely needed. In this issue, Zhu et al. (2015) report the use of a Caenorhabditis elegans model to validate the Pseudomonas aeruginosa virulence factor LasB as a potential therapeutic target and to identify a LasB inhibitor with in vivo efficacy.}, number={4}, journal={CHEMISTRY & BIOLOGY}, author={Melander, Roberta J. and Melander, Christian}, year={2015}, month={Apr}, pages={436–437} }
 @article{garrido_simpson_dahl_bresee_whitehead_lindsey_harris_smith_carter_feldheim_et al._2015, title={Gold nanoparticles to improve HIV drug delivery}, volume={7}, ISSN={["1756-8927"]}, DOI={10.4155/fmc.15.57}, abstractNote={ Background: Antiretroviral therapy (ART) has improved lifespan and quality of life of patients infected with the HIV-1. However, ART has several potential limitations, including the development of drug resistance and suboptimal penetration to selected anatomic compartments. Improving the delivery of antiretroviral molecules could overcome several of the limitations of current ART. Results & Conclusion: Two to ten nanometer diameter inorganic gold crystals serve as a base scaffold to combine molecules with an array of properties in its surface. We show entry into different cell types, antiviral activity of an HIV integrase inhibitor conjugated in a gold nanoparticle and penetration into the brain in vivo without toxicity. Herein, gold nanoparticles prove to be a promising tool to use in HIV therapy. }, number={9}, journal={FUTURE MEDICINAL CHEMISTRY}, author={Garrido, Carolina and Simpson, Carrie A. and Dahl, Noelle P. and Bresee, Jamee and Whitehead, Daniel C. and Lindsey, Erick A. and Harris, Tyler L. and Smith, Candice A. and Carter, Carly J. and Feldheim, Daniel L. and et al.}, year={2015}, pages={1097–1107} }
 @article{richardson_furlani_podell_ackart_haugen_melander_melander_basaraba_2015, title={Inhibition and breaking of advanced glycation end-products (AGEs) with bis-2-aminoimidazole derivatives}, volume={56}, ISSN={["0040-4039"]}, DOI={10.1016/j.tetlet.2015.01.122}, abstractNote={Advanced glycation end-products (AGEs), unregulated modifications to host macromolecules that occur as a result of metabolic dysregulation, play a role in many diabetes related complications, inflammation and aging, and may lead to increased cardiovascular risk. Small molecules that have the ability to inhibit AGE formation, and even break preformed AGEs have enormous therapeutic potential in the treatment of these disease states. We report the screening of a series of 2-aminoimidazloles for anti-AGE activity, and the identification of a bis-2-aminoimidazole lead compound that possesses superior AGE inhibition and breaking activity compared to the known AGE inhibitor aminoguanidine.}, number={23}, journal={TETRAHEDRON LETTERS}, author={Richardson, Mike A. and Furlani, Robert E. and Podell, Brendan K. and Ackart, David F. and Haugen, Jessica D. and Melander, Roberta J. and Melander, Christian and Basaraba, Randall J.}, year={2015}, month={Jun}, pages={3406–3409} }
 @article{melander_melander_2015, title={Innovative strategies for combating biofilm-based infections}, volume={831}, journal={Biofilm-based healthcare-associated infections, vol ii}, author={Melander, R. J. and Melander, C.}, year={2015}, pages={69–91} }
 @article{stowe_thompson_peng_su_blackledge_draughn_coe_johannes_lapham_mackenzie_et al._2015, title={Membrane-Permeabilizing Activity of Reverse-Amide 2-Aminoimidazole Antibiofilm Agents Against Acinetobacter baumannii}, volume={12}, ISSN={["1875-5704"]}, DOI={10.2174/1567201811666140924125740}, abstractNote={Acinetobacter baumannii has quickly become one of the most insidious and prevalent nosocomial infections. Recently, the reverse-amide class of 2-aminoimidazole compounds (RA-2AI) was found both to prevent A. baumannii biofilm formation and also to disperse preexisting formations, putatively through interactions with cytosolic response regulators. Here we focus on how this class of antibiofilm agent traverses cellular membranes. Following the discovery of dosage-dependent growth rate changes, the cellular effects of RA-2AI were investigated using a combination of molecular assays and microscopic techniques. It was found that RA-2AI exposure has measureable effects on the bacterial membranes, resulting in a period of increased permeability and visible structural aberrations. Based on these results, we propose a model that describes how the structure of RA-2AI allows it to insert itself into and disrupt the fluidity of the membrane, creating an opportunity for increased molecular permeability.}, number={2}, journal={CURRENT DRUG DELIVERY}, author={Stowe, Sean D. and Thompson, Richele J. and Peng, Lingling and Su, Zhaoming and Blackledge, Meghan S. and Draughn, G. Logan and Coe, William H. and Johannes, Eva and Lapham, Valerie K. and Mackenzie, John and et al.}, year={2015}, pages={223–230} }
 @article{furlani_richardson_podell_ackart_haugen_melander_basaraba_melander_2015, title={Second generation 2-aminoimidazole based advanced glycation end product inhibitors and breakers}, volume={25}, ISSN={["1464-3405"]}, DOI={10.1016/j.bmcl.2015.06.080}, abstractNote={The formation of advanced glycation end-products (AGE) as a result of the action of reducing sugars on host macromolecules plays a role in increased morbidity of diabetic patients. There are currently no clinically available therapeutics for the prevention or eradication of AGEs. Following our previous identification of 2-aminoimidazole (2-AI) based AGE inhibitors and breakers, we now report the use of a rapid, scalable, two-step procedure to access a second generation of 2-AI based anti-AGE compounds from commercially available amino acids. Several second generation compounds exhibit increased AGE inhibition and breaking activty compared to the first generation compounds and to the known AGE inhibitor aminoguanidine.}, number={21}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Furlani, Robert E. and Richardson, Mike A. and Podell, Brendan K. and Ackart, David F. and Haugen, Jessica D. and Melander, Roberta J. and Basaraba, Randall J. and Melander, Christian}, year={2015}, month={Nov}, pages={4820–4823} }
 @article{melander_minvielle_melander_2014, title={Controlling bacterial behavior with indole-containing natural products and derivatives}, volume={70}, ISSN={["0040-4020"]}, DOI={10.1016/j.tet.2014.05.089}, abstractNote={Indole has recently been implicated as an important small molecule signal utilized by many bacteria to coordinate various forms of behavior. Indole plays a role in numerous bacterial processes, including: biofilm formation and maintenance, virulence factor production, antibiotic resistance and persister cell formation. Intercepting indole-signaling pathways with appropriately designed small molecules provides a n opportunity to control unwanted bacterial behaviors, and is an attractive anti-virulence therapeutic strategy. In this review, we give an overview of the process controlled by indole signaling, and summarize current efforts to design indole-containing small molecules to intercept these pathways, and detail the synthetic efforts towards accessing indole derived bioactive small molecules.}, number={37}, journal={TETRAHEDRON}, author={Melander, Roberta J. and Minvielle, Marine J. and Melander, Christian}, year={2014}, month={Sep}, pages={6363–6372} }
 @article{ackart_hascall-dove_caceres_kirk_podell_melander_orme_leid_nick_basaraba_2014, title={Expression of antimicrobial drug tolerance by attached communities of Mycobacterium tuberculosis}, volume={70}, ISSN={["2049-632X"]}, DOI={10.1111/2049-632x.12144}, abstractNote={There is an urgent need to improve methods used to screen antituberculosis drugs. An in vitro assay was developed to test drug treatment strategies that specifically target drug-tolerant Mycobacterium tuberculosis. The H37Rv strain of M. tuberculosis survived antimicrobial treatment as attached microbial communities when maintained in tissue culture media (RPMI-1640) with or without lysed human peripheral blood leukocytes. When cultured planktonically in the presence of Tween-80, bacilli failed to form microbial communities or reach logarithmic phase growth yet remained highly susceptible to antimicrobial drugs. In the absence of Tween, bacilli tolerated drug therapy by forming complex microbial communities attached to untreated well surfaces or to the extracellular matrix derived from lysed human leukocytes. Treatment of microbial communities with DNase I or Tween effectively dispersed bacilli and restored drug susceptibility. These data demonstrate that in vitro expression of drug tolerance by M. tuberculosis is linked to the establishment of attached microbial communities and that dispersion of bacilli targeting the extracellular matrix including DNA restores drug susceptibility. Modifications of this in vitro assay may prove beneficial in a high-throughput platform to screen new antituberculosis drugs especially those that target drug-tolerant bacilli.}, number={3}, journal={PATHOGENS AND DISEASE}, author={Ackart, David F. and Hascall-Dove, Laurel and Caceres, Silvia M. and Kirk, Natalie M. and Podell, Brendan K. and Melander, Christian and Orme, Ian M. and Leid, Jeff G. and Nick, Jerry A. and Basaraba, Randall J.}, year={2014}, month={Apr}, pages={359–369} }
 @article{bresee_bond_worthington_smith_gifford_simpson_carter_wang_hartman_osbaugh_et al._2014, title={Nanoscale Structure-Activity Relationships, Mode of Action, and Biocompatibility of Gold Nanoparticle Antibiotics}, volume={136}, ISSN={["0002-7863"]}, DOI={10.1021/ja408505n}, abstractNote={The emergence of resistance to multiple antimicrobial agents by pathogenic bacteria has become a significant global public health threat. Multi-drug-resistant (MDR) Gram-negative bacteria have become particularly problematic, as no new classes of small-molecule antibiotics for Gram-negative bacteria have emerged in over two decades. We have developed a combinatorial screening process for identifying mixed ligand monolayer/gold nanoparticle conjugates (2.4 nm diameter) with antibiotic activity. The method previously led to the discovery of several conjugates with potent activity against the Gram-negative bacterium Escherichia coli. Here we show that these conjugates are also active against MDR E. coli and MDR Klebsiella pneumoniae. Moreover, we have shown that resistance to these nanoparticles develops significantly more slowly than to a commercial small-molecule drug. These results, combined with their relatively low toxicity to mammalian cells and biocompatibility in vivo, suggest that gold nanoparticles may be viable new candidates for the treatment of MDR Gram-negative bacterial infections.}, number={14}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Bresee, Jamee and Bond, Constance M. and Worthington, Roberta J. and Smith, Candice A. and Gifford, Jennifer C. and Simpson, Carrie A. and Carter, Carly J. and Wang, Guankui and Hartman, Jesse and Osbaugh, Niki A. and et al.}, year={2014}, month={Apr}, pages={5295–5300} }
 @article{ackart_lindsey_podell_melander_basaraba_melander_2014, title={Reversal of Mycobacterium tuberculosis phenotypic drug resistance by 2-aminoimidazole- based small molecules}, volume={70}, ISSN={["2049-632X"]}, DOI={10.1111/2049-632x.12143}, abstractNote={The expression of phenotypic drug resistance or drug tolerance serves as a strategy for Mycobacterium tuberculosis to survive in vivo antimicrobial drug treatment; however, the mechanisms are poorly understood. Progress toward a more in depth understanding of in vivo drug tolerance and the discovery of new therapeutic strategies designed specifically to treat drug-tolerant M. tuberculosis are hampered by the lack of appropriate in vitro assays. A library of 2-aminoimidazole-based small molecules combined with the antituberculosis drug isoniazid was screened against M. tuberculosis expressing in vitro drug tolerance as microbial communities attached to an extracellular matrix derived from lysed leukocytes. Based on the ability of nine of ten 2-aminoimidazole compounds to inhibit Mycobacterium smegmatis biofilm formation and three of ten molecules capable of dispersing established biofilms, two active candidates and one inactive control were tested against drug-tolerant M. tuberculosis. The two active compounds restored isoniazid susceptibility as well as reduced the in vitro minimum inhibitory concentrations of isoniazid in a dose-dependent manner. The dispersion of drug-tolerant M. tuberculosis with 2-aminoimidazole-based small molecules as an adjunct to antimicrobial treatment has the potential to be an effective antituberculosis treatment strategy designed specifically to eradicate drug-tolerant M. tuberculosis.}, number={3}, journal={PATHOGENS AND DISEASE}, author={Ackart, David F. and Lindsey, Erick A. and Podell, Brendan K. and Melander, Roberta J. and Basaraba, Randall J. and Melander, Christian}, year={2014}, month={Apr}, pages={370–378} }
 @article{harris_worthington_hittle_zurawski_ernst_melander_2014, title={Small Molecule Downregulation of PmrAB Reverses Lipid A Modification and Breaks Colistin Resistance}, volume={9}, ISSN={["1554-8937"]}, DOI={10.1021/cb400490k}, abstractNote={Infections caused by multi-drug resistant bacteria, particularly Gram-negative bacteria, are an ever-increasing problem. While the development of new antibiotics remains one option in the fight against bacteria that have become resistant to currently available antibiotics, an attractive alternative is the development of adjuvant therapeutics that restore the efficacy of existing antibiotics. We report a small molecule adjuvant that suppresses colistin resistance in multidrug resistant Acinetobacter baumannii and Klebsiella pneumoniae by interfering with the expression of a two-component system. The compound downregulates the pmrCAB operon and reverses phosphoethanolamine modification of lipid A responsible for colistin resistance. Furthermore, colistin-susceptible and colistin-resistant bacteria do not evolve resistance to combination treatment. This represents the first definitive example of a compound that breaks antibiotic resistance by directly modulating two-component system activity.}, number={1}, journal={ACS CHEMICAL BIOLOGY}, author={Harris, Tyler L. and Worthington, Roberta J. and Hittle, Lauren E. and Zurawski, Daniel V. and Ernst, Robert K. and Melander, Christian}, year={2014}, month={Jan}, pages={122–127} }
 @article{brackett_melander_an_krishnamurthy_thompson_cavanagh_melander_2014, title={Small-Molecule Suppression of beta-Lactam Resistance in Multidrug-Resistant Gram-Negative Pathogens}, volume={57}, ISSN={["1520-4804"]}, DOI={10.1021/jm501050e}, abstractNote={Recent efforts toward combating antibiotic resistance in bacteria have focused on Gram-positive bacteria; however, multidrug-resistant Gram-negative bacteria pose a significant risk to public health. An orthogonal approach to the development of new antibiotics is to develop adjuvant compounds that enhance the susceptibility of drug-resistant strains of bacteria to currently approved antibiotics. This paper describes the synthesis and biological activity of a library of aryl amide 2-aminoimidazoles based on a lead structure from an initial screen. A small molecule was identified from this library that is capable of lowering the minimum inhibitory concentration of β-lactam antibiotics by up to 64-fold.}, number={17}, journal={JOURNAL OF MEDICINAL CHEMISTRY}, author={Brackett, Christopher M. and Melander, Roberta J. and An, Il Hwan and Krishnamurthy, Aparna and Thompson, Richele J. and Cavanagh, John and Melander, Christian}, year={2014}, month={Sep}, pages={7450–7458} }
 @article{gifford_bresee_carter_wang_melander_melander_feldheim_2014, title={Thiol-modified gold nanoparticles for the inhibition of Mycobacterium smegmatis}, volume={50}, ISSN={["1364-548X"]}, DOI={10.1039/c4cc06236a}, abstractNote={We demonstrate that Small Molecule Variable Ligand Display expanded around feed ratio parameter space identified gold nanoparticle conjugates that are potent inhibitors of mycobacterium growth, addressing a lack of innovative approaches to treat infections caused by mycobacteria such as TB.}, number={100}, journal={CHEMICAL COMMUNICATIONS}, author={Gifford, Jennifer C. and Bresee, Jamee and Carter, Carly Jo and Wang, Guankui and Melander, Roberta J. and Melander, Christian and Feldheim, Daniel L.}, year={2014}, pages={15860–15863} }
 @article{furlani_yeagley_melander_2013, title={A flexible approach to 1,4-di-substituted 2-aminoimidazoles that inhibit and disperse biofilms and potentiate the effects of beta-lactams against multi-drug resistant bacteria}, volume={62}, ISSN={["1768-3254"]}, DOI={10.1016/j.ejmech.2012.12.005}, abstractNote={The pyrrole-imidazole alkaloids are a 2-aminoimidazoles containing family of natural products that possess anti-biofilm activity. A library of 1,4-di-substituted 2-aminoimidazole/triazoles (2-AITs) was synthesized, and its anti-biofilm activity as well as oxacillin resensitization efficacy toward methicillin resistant Staphylococcus aureus (MRSA) was investigated. These 2-AITs were found to inhibit biofilm formation by MRSA with low micromolar IC50 values. Additionally, the most active compound acted synergistically with oxacillin against MRSA lowering the minimum inhibitory concentration (MIC) 4-fold.}, journal={EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}, author={Furlani, Robert E. and Yeagley, Andrew A. and Melander, Christian}, year={2013}, month={Apr}, pages={59–70} }
 @article{blackledge_worthington_melander_2013, title={Biologically inspired strategies for combating bacterial biofilms}, volume={13}, ISSN={["1471-4973"]}, DOI={10.1016/j.coph.2013.07.004}, abstractNote={Infections caused by bacterial biofilms are a significant global health problem, causing considerable patient morbidity and mortality and contributing to the economic burden of infectious disease. This review describes diverse strategies to combat bacterial biofilms, focusing firstly on small molecule interference with bacterial communication and signaling pathways, including quorum sensing and two-component signal transduction systems. Secondly we discuss enzymatic approaches to the degradation of extracellular matrix components to effect biofilm dispersal. Both of these approaches are based upon non-microbicidal mechanisms of action, and thereby do not place a direct evolutionary pressure on the bacteria to develop resistance. Such approaches have the potential to, in combination with conventional antibiotics, play an important role in the eradication of biofilm based bacterial infections.}, number={5}, journal={CURRENT OPINION IN PHARMACOLOGY}, author={Blackledge, Meghan S. and Worthington, Roberta J. and Melander, Christian}, year={2013}, month={Oct}, pages={699–706} }
 @misc{worthington_melander_2013, title={Combination approaches to combat multidrug-resistant bacteria}, volume={31}, ISSN={["1879-3096"]}, DOI={10.1016/j.tibtech.2012.12.006}, abstractNote={The increasing prevalence of infections caused by multidrug-resistant bacteria is a global health problem that has been exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein, we describe recent developments toward combination therapies for the treatment of multidrug-resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems (TCSs). We also discuss screening of libraries of previously approved drugs to identify nonobvious antimicrobial adjuvants.}, number={3}, journal={TRENDS IN BIOTECHNOLOGY}, author={Worthington, Roberta J. and Melander, Christian}, year={2013}, month={Mar}, pages={177–184} }
 @article{minvielle_eguren_melander_2013, title={Highly Active Modulators of Indole Signaling Alter Pathogenic Behaviors in Gram-Negative and Gram-Positive Bacteria}, volume={19}, ISSN={["1521-3765"]}, DOI={10.1002/chem.201303510}, abstractNote={Abstract}, number={51}, journal={CHEMISTRY-A EUROPEAN JOURNAL}, author={Minvielle, Marine J. and Eguren, Kristen and Melander, Christian}, year={2013}, month={Dec}, pages={17595–17602} }
 @article{minvielle_bunders_melander_2013, title={Indole-triazole conjugates are selective inhibitors and inducers of bacterial biofilms}, volume={4}, ISSN={["2040-2511"]}, DOI={10.1039/c3md00064h}, abstractNote={Herein is described a method of accessing indole/triazole and benzothiophene/triazole analogues that selectively promote or inhibit biofilm formation by Gram-positive and Gram-negative bacteria. Structure/function studies revealed that the addition of a bromine atom at the 2-position of the indole/triazole scaffold altered activity against both Gram-negative and Gram-positive bacteria and could transform a biofilm inhibitor into a biofilm inducer. Isosteric replacement of the indole core by a benzothiophene significantly impaired anti-biofilm activity. A competition assay exposing Escherichia coli to the most potent biofilm inducer and an inhibitor of E. coli biofilm formation was performed. The inducer exhibited the ability to mute the effect of the anti-biofilm compound for this targeted bacterial population.}, number={6}, journal={MEDCHEMCOMM}, author={Minvielle, Marine J. and Bunders, Cynthia A. and Melander, Christian}, year={2013}, month={Jun}, pages={916–919} }
 @article{yeagley_su_mccullough_worthington_melander_2013, title={N-Substituted 2-aminoimidazole inhibitors of MRSA biofilm formation accessed through direct 1,3-bis(tert-butoxycarbonyl)guanidine cyclization}, volume={11}, ISSN={["1477-0539"]}, DOI={10.1039/c2ob26469b}, abstractNote={Antibiotic resistance is a significant problem and is compounded by the ability of many pathogenic bacteria to form biofilms. A library of N-substituted derivatives of a previously reported 2-aminoimidazole/triazole (2-AIT) biofilm modulator was constructed via α-bromoketone cyclization with 1,3-bis(tert-butoxycarbonyl)guanidine, followed by selective substitution. Several compounds exhibited the ability to inhibit biofilm formation by three strong biofilm forming strains of methicillin resistant Staphylococcus aureus (MRSA). Additionally, a number of members of this library exhibited synergistic activity with oxacillin against planktonic MRSA. Compounds with this type of dual activity have the potential to be used as adjuvants with conventional antibiotics.}, number={1}, journal={ORGANIC & BIOMOLECULAR CHEMISTRY}, author={Yeagley, Andrew A. and Su, Zhaoming and McCullough, Kara D. and Worthington, Roberta J. and Melander, Christian}, year={2013}, pages={130–137} }
 @article{worthington_melander_2013, title={Overcoming Resistance to beta-Lactam Antibiotics}, volume={78}, ISSN={["1520-6904"]}, DOI={10.1021/jo400236f}, abstractNote={β-Lactam antibiotics are one of the most important antibiotic classes but are plagued by problems of resistance, and the development of new β-lactam antibiotics through side-chain modification of existing β-lactam classes is not keeping pace with resistance development. In this JOCSynopsis, we summarize small molecule strategies to overcome resistance to β-lactam antibiotics. These approaches include the development of β-lactamase inhibitors and compounds that interfere with the ability of the bacteria to sense an antibiotic threat and activate their resistance mechanisms.}, number={9}, journal={JOURNAL OF ORGANIC CHEMISTRY}, author={Worthington, Roberta J. and Melander, Christian}, year={2013}, month={May}, pages={4207–4213} }
 @article{blackledge_melander_2013, title={Programmable DNA-binding small molecules}, volume={21}, ISSN={["0968-0896"]}, DOI={10.1016/j.bmc.2013.04.023}, abstractNote={Aberrant gene expression is responsible for a myriad of human diseases from infectious diseases to cancer. Precise regulation of these genes via specific interactions with the DNA double helix could pave the way for novel therapeutics. Pyrrole-imidazole polyamides are small molecules capable of binding to pre-determined DNA sequences up to 16 base pairs with affinity and specificity comparable to natural transcription factors. In the three decades since their development, great strides have been made relating to synthetic accessibility and improved sequence specificity and binding affinity. This perspective presents a brief history of early seminal developments in the field and highlights recent reports of the utility of polyamides as both genetic modulators and molecular probes.}, number={20}, journal={BIOORGANIC & MEDICINAL CHEMISTRY}, author={Blackledge, Meghan S. and Melander, Christian}, year={2013}, month={Oct}, pages={6101–6114} }
 @misc{worthington_blackledge_melander_2013, title={Small-molecule inhibition of bacterial two-component systems to combat antibiotic resistance and virulence}, volume={5}, ISSN={["1756-8927"]}, DOI={10.4155/fmc.13.58}, abstractNote={ Infections caused by multidrug-resistant bacteria are a considerable and increasing global problem. The development of new antibiotics is not keeping pace with the rapid evolution of resistance to almost all clinically available drugs, and novel strategies are required to fight bacterial infections. One such strategy is the control of pathogenic behaviors, as opposed to simply killing bacteria. Bacterial two-component system (TCS) signal transduction pathways control many pathogenic bacterial behaviors, such as virulence, biofilm formation and antibiotic resistance and are, therefore, an attractive target for the development of new drugs. This review presents an overview of TCS that are potential targets for such a strategy, describes small-molecules inhibitors of TCS identified to date and discusses assays for the identification of novel inhibitors. The future perspective for the identification and use of inhibitors of TCS to potentially provide new therapeutic options for the treatment of drug-resistant bacterial infections is discussed. }, number={11}, journal={FUTURE MEDICINAL CHEMISTRY}, author={Worthington, Roberta J. and Blackledge, Meghan S. and Melander, Christian}, year={2013}, month={Jul}, pages={1265–1284} }
 @article{lindsey_worthington_alcaraz_melander_2012, title={2-Aminopyrimidine as a novel scaffold for biofilm modulation}, volume={10}, number={13}, journal={Organic & Biomolecular Chemistry}, author={Lindsey, E. A. and Worthington, R. J. and Alcaraz, C. and Melander, C.}, year={2012}, pages={2552–2561} }
 @article{su_peng_melander_2012, title={A modular approach to the synthesis of 1,4,5-substituted-2-aminoimidazoles}, volume={53}, ISSN={["0040-4039"]}, DOI={10.1016/j.tetlet.2011.12.090}, abstractNote={Diversified 1,4,5-substituted-2-aminoimidazoles were rapidly assembled via sequential N–H insertion and Grignard addition to α-diazoesters. Lead compounds were identified as antibiotics against Gram-positive bacteria with an MIC value as low as 2 μg/mL.}, number={10}, journal={TETRAHEDRON LETTERS}, author={Su, Zhaoming and Peng, Lingling and Melander, Christian}, year={2012}, month={Mar}, pages={1204–1206} }
 @article{worthington_melander_2012, title={Deconvoluting Interspecies Bacterial Communication}, volume={51}, ISSN={["1433-7851"]}, DOI={10.1002/anie.201202440}, abstractNote={The universal bacterial signal molecule autoinducer-2 (AI-2) is derived from 4,5-dihydroxy-2,3-pentanedione (DPD). DPD exists in a complex equilibrium between multiple forms, and NMR spectroscopy has now been used to establish that the extent of the structural diversity displayed by DPD over a broad pH range is even greater than previously posited.}, number={26}, journal={ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}, author={Worthington, Roberta J. and Melander, Christian}, year={2012}, pages={6314–6315} }
 @article{stowe_tucker_thompson_piper_richards_rogers_mathies_melander_cavanagh_2012, title={Evaluation of the toxicity of 2-aminoimidazole antibiofilm agents using both cellular and model organism systems}, volume={35}, ISSN={["1525-6014"]}, DOI={10.3109/01480545.2011.614620}, abstractNote={Biofilm formation is a ubiquitous bacterial defense mechanism and has been shown to be a primary element in the antibiotic resistance of many human diseases, especially in the case of nosocomial infections. Recently, we have developed several compound libraries that are extremely effective at both dispersing preexisting biofilms and also inhibiting their initial formation. In addition to their antibiofilm properties, some of these molecules are able to resensitize resistant bacterial strains to previously ineffective antibiotics and are being assessed as adjuvants. In this study, we evaluated the toxic effects of three of our most effective 2-aminoimidazole compounds (dihydrosventrin, RA, and SPAR) using a rapid pipeline that combines a series of assays. A methylthiazolyldiphenyl-tetrazolium assay, using the HaCaT keratinocyte cell line was used to determine epidermal irritants and was combined with Caenorhabditis elegans fecundity assays that demonstrated the effects of environmental exposure to various concentrations of these molecules. In each case, the assays showed that the compounds did not exhibit toxicity until they reached well above their current biofilm dispersion/inhibition concentrations. The most effective antibiofilm compound also had significant effects when used in conjunction with several standard antibiotics against resistant bacteria. Consequently, it was further investigated using the C. elegans assay in combination with different antibiotics and was found to maintain the same low level of toxicity as when acting alone, bolstering its candidacy for further testing as an adjuvant.}, number={3}, journal={DRUG AND CHEMICAL TOXICOLOGY}, author={Stowe, Sean D. and Tucker, Ashley T. and Thompson, Richele and Piper, Amanda and Richards, Justin J. and Rogers, Steven A. and Mathies, Laura D. and Melander, Christian and Cavanagh, John}, year={2012}, month={Jul}, pages={310–315} }
 @article{worthington_rogers_huigens_melander_ritchie_2012, title={Foliar-Applied Small Molecule that Suppresses Biofilm Formation and Enhances Control of Copper-Resistant Xanthomonas euvesicatoria on Pepper}, volume={96}, ISSN={["1943-7692"]}, DOI={10.1094/pdis-02-12-0190-re}, abstractNote={ We report a small molecule additive, a member of the 2-aminoimidazole (2AI) group that is an analogue of the marine sponge natural product oroidin that suppresses resistance of Xanthomonas euvesicatoria to copper and decreases biofilm formation in an in vitro system. In laboratory experiments, 2AI combined with copper reduced both bacterial multiplication in broth and bacterial recovery on pepper leaf discs of a copper-resistant strain of X. euvesicatoria to a level close to that of a copper-sensitive strain. Compound 2AI used alone exhibited minimal bactericidal activity. In 3 years of field experiments, when combined with a copper-containing material, copper hydroxide (Kocide 3000), and other antibacterial materials, these spray mixtures resulted in decreased bacterial spot foliar disease and increased fruit yields using hybrid bell pepper (Capsicum annuum) cultivars and copper-resistant strains of X. euvesicatoria. This study demonstrates the concept for using small molecules as additives to antibacterial compounds at nonbactericidal concentrations under field conditions that, in the laboratory, were demonstrated to suppress bacterial biofilms and copper-resistant strains. }, number={11}, journal={PLANT DISEASE}, author={Worthington, R. J. and Rogers, S. A. and Huigens, R. W., III and Melander, C. and Ritchie, D. F.}, year={2012}, month={Nov}, pages={1638–1644} }
 @article{olson_bobay_melander_cavanagh_2012, title={H-1, C-13, and N-15 resonance assignments and secondary structure prediction of the full-length transition state regulator AbrB from Bacillus anthracis}, volume={6}, ISSN={["1874-2718"]}, DOI={10.1007/s12104-011-9333-2}, abstractNote={The AbrB protein is a transcription factor that regulates the expression of numerous essential genes during the cells transition phase state. AbrB from Bacillus anthracis is, nototriously, the principal protein responsible for anthrax toxin gene expression and is highly homologous to the much-studied AbrB protein from Bacillus subtilis having 85% sequence identity and the ability to regulate the same target promoters. Here we report backbone and sidechain resonance assignments and secondary structure prediction for the full-length AbrB protein from B. anthracis.}, number={1}, journal={BIOMOLECULAR NMR ASSIGNMENTS}, author={Olson, Andrew L. and Bobay, Benjamin G. and Melander, Christian and Cavanagh, John}, year={2012}, month={Apr}, pages={95–98} }
 @article{thompson_bobay_stowe_olson_peng_su_actis_melander_cavanagh_2012, title={Identification of BfmR, a Response Regulator Involved in Biofilm Development, as a Target for a 2-Aminoimidazole-Based Antibiofilm Agent}, volume={51}, ISSN={["0006-2960"]}, DOI={10.1021/bi3015289}, abstractNote={2-Aminoimidazoles (2AIs) have been documented to disrupt bacterial protection mechanisms, including biofilm formation and genetically encoded antibiotic resistance traits. Using Acinetobacter baumannii, we provide initial insight into the mechanism of action of a 2AI-based antibiofilm agent. Confocal microscopy confirmed that the 2AI is cell permeable, while pull-down assays identified BfmR, a response regulator that is the master controller of biofilm formation, as a target for this compound. Binding assays demonstrated specificity of the 2AI for response regulators, while computational docking provided models for 2AI-BfmR interactions. The 2AI compound studied here represents a unique small molecule scaffold that targets bacterial response regulators.}, number={49}, journal={BIOCHEMISTRY}, author={Thompson, Richele J. and Bobay, Benjamin G. and Stowe, Sean D. and Olson, Andrew L. and Peng, Lingling and Su, Zhaoming and Actis, Luis A. and Melander, Christian and Cavanagh, John}, year={2012}, month={Dec}, pages={9776–9778} }
 @article{melander_margolis_2012, title={Medicinal chemistry: Forcing an enemy into the open}, volume={4}, number={9}, journal={Nature Chemistry}, author={Melander, C. and Margolis, D. M.}, year={2012}, pages={692–693} }
 @article{harris_worthington_melander_2012, title={Potent Small-Molecule Suppression of Oxacillin Resistance in Methicillin-Resistant Staphylococcus aureus}, volume={51}, ISSN={["1521-3773"]}, DOI={10.1002/anie.201206911}, abstractNote={Shields down! Adjuvant molecules that have the ability to restore the susceptibility of multi-drug-resistant bacteria, such as MRSA, to clinically available antibiotics are a promising alternative to the development of novel antimicrobials. Pictured is a potent small molecule (1) that, at sub-minimum inhibitory concentration (sub-MIC) levels, lowers the MIC of oxacillin (2) against a number of MRSA strains by up to 512-fold.}, number={45}, journal={ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}, author={Harris, Tyler L. and Worthington, Roberta J. and Melander, Christian}, year={2012}, pages={11254–11257} }
 @article{worthington_bunders_reed_melander_2012, title={Small Molecule Suppression of Carbapenem Resistance in NDM-1 Producing Klebsiella pneumoniae}, volume={3}, ISSN={["1948-5875"]}, DOI={10.1021/ml200290p}, abstractNote={The already considerable global public health threat of multi-drug resistant Gram-negative bacteria has become even more of a concern following the emergence of New-Delhi metallo-β-lactamase (NDM-1) producing strains of Klebsiella pneumoniae and other Gram-negative bacteria. As an alternative approach to the traditional development of new bactericidal entities, we have identified a 2-aminoimidazole derived small molecule that acts as an antibiotic adjuvant and is able to suppress resistance of a NDM-1 producing strain of K. pneumoniae to imipenem and meropenem, in addition to suppressing resistance of other β-lactam non-susceptible K. pneumoniae strains. The small molecule is able to lower carbapenem minimum inhibitory concentrations by up to 16-fold while exhibiting little bactericidal activity itself.}, number={5}, journal={ACS MEDICINAL CHEMISTRY LETTERS}, author={Worthington, Roberta J. and Bunders, Cynthia A. and Reed, Catherine S. and Melander, Christian}, year={2012}, month={May}, pages={357–361} }
 @article{worthington_richards_melander_2012, title={Small molecule control of bacterial biofilms}, volume={10}, number={37}, journal={Organic & Biomolecular Chemistry}, author={Worthington, R. J. and Richards, J. J. and Melander, C.}, year={2012}, pages={7457–7474} }
 @article{budhathoki-uprety_peng_melander_novak_2012, title={Synthesis of Guanidinium Functionalized Polycarbodiimides and Their Antibacterial Activities}, volume={1}, ISSN={["2161-1653"]}, url={http://dx.doi.org/10.1021/mz200116k}, DOI={10.1021/mz200116k}, abstractNote={A family of guanidinium-side-chain functionalized polycarbodiimides has been synthesized by allowing an azido guanidinium salt to react with alkyne polycarbodiimides via the copper catalyzed [3 + 2] cycloaddition (Click) reaction. Poly-2(a-d) are cationic/amphiphilic polymers in which the global hydrophilic/hydrophobic balance has been tailored by local alteration of the length of alkyl side chain in the repeat unit of polymers prior to polymerization. The shorter alkyl chains yield water-soluble polymers, Poly-2c, -2d, and -2e. Antibacterial activities of these cationic polycarbodiimides have been investigated for Gram-positive and Gram-negative bacteria that include Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Acinetobacter baumannii. It was observed that the influence of hydrophobic-hydrophilic balance per repeat unit of these polymers have profound effects for both antimicrobial and hemolytic activities. In addition, these polycarbodiimide-guanidinium-triazole conjugates offered moderate to significant antibacterial activity and rapid interaction with red blood cells causing blood precipitation without significant hemolysis in case of Poly-2(b-e). This latter property has the potential to be exploited in the polymer coatings or wound protection.}, number={3}, journal={ACS MACRO LETTERS}, author={Budhathoki-Uprety, Januka and Peng, LingLing and Melander, Christian and Novak, Bruce M.}, year={2012}, month={Mar}, pages={370–374} }
 @article{liu_worthington_melander_wu_2011, title={A New Small Molecule Specifically Inhibits the Cariogenic Bacterium Streptococcus mutans in Multispecies Biofilms}, volume={55}, ISSN={["0066-4804"]}, DOI={10.1128/aac.01496-10}, abstractNote={ABSTRACT}, number={6}, journal={ANTIMICROBIAL AGENTS AND CHEMOTHERAPY}, author={Liu, Chang and Worthington, Roberta J. and Melander, Christian and Wu, Hui}, year={2011}, month={Jun}, pages={2679–2687} }
 @article{harris_worthington_melander_2011, title={A facile synthesis of 1,5-disubstituted-2-aminoimidazoles: Antibiotic activity of a first generation library}, volume={21}, ISSN={["1464-3405"]}, DOI={10.1016/j.bmcl.2011.05.123}, abstractNote={An efficient synthetic route to 1,5-disubstituted 2-aminoimidazoles from readily available amino acids and aldehydes has been developed. A library of simple analogues was synthesized and several compounds were shown to exhibit notable antibiotic activity against a variety of bacterial strains including multi-drug resistant isolates.}, number={15}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Harris, Tyler L. and Worthington, Roberta J. and Melander, Christian}, year={2011}, month={Aug}, pages={4516–4519} }
 @misc{stowe_richards_tucker_thompson_melander_cavanagh_2011, title={Anti-biofilm compounds derived from marine sponges}, volume={9}, number={10}, journal={Marine Drugs}, author={Stowe, S. D. and Richards, J. J. and Tucker, A. T. and Thompson, R. and Melander, C. and Cavanagh, J.}, year={2011}, pages={2010–2035} }
 @article{su_peng_worthington_melander_2011, title={Evaluation of 4,5-Disubstituted-2-Aminoimidazole-Triazole Conjugates for Antibiofilm/Antibiotic Resensitization Activity Against MRSA and Acinetobacter baumannii}, volume={6}, ISSN={["1860-7187"]}, DOI={10.1002/cmdc.201100316}, abstractNote={Abstract}, number={12}, journal={CHEMMEDCHEM}, author={Su, Zhaoming and Peng, Lingling and Worthington, Roberta J. and Melander, Christian}, year={2011}, month={Dec}, pages={2243–2251} }
 @article{bunders_cavanagh_melander_2011, title={Flustramine inspired synthesis and biological evaluation of pyrroloindoline triazole amides as novel inhibitors of bacterial biofilms}, volume={9}, ISSN={["1477-0539"]}, DOI={10.1039/c1ob05605k}, abstractNote={Anti-biofilm agents have been developed based upon the flustramine family of alkaloids isolated from Flustra foliacea. A Garg interrupted Fischer indolization reaction was employed to access a core pyrroloindoline scaffold that was subsequently employed to create a pyrroloindoline triazole amide library. Screening for the ability to modulate biofilm formation against strains of Gram-positive and Gram-negative bacteria identified several compounds with low micromolar, non-toxic IC(50) values.}, number={15}, journal={ORGANIC & BIOMOLECULAR CHEMISTRY}, author={Bunders, Cynthia and Cavanagh, John and Melander, Christian}, year={2011}, pages={5476–5481} }
 @article{bresee_maier_boncella_melander_feldheim_2011, title={Growth Inhibition of Staphylococcus aureus by Mixed Monolayer Gold Nanoparticles}, volume={7}, ISSN={["1613-6829"]}, DOI={10.1002/smll.201100420}, abstractNote={A library of 120 nanoparticle conjugates is produced by simple one-pot thiol exchange reactions. The antibiotic activity of the conjugates toward Staphylococcus aureus is found to depend upon the combination of thiols assembled on the nanoparticles. Synthetic nanometer-scale systems have the potential to overcome many limitations of conventional small-molecule therapeutic agents.1 For instance, small molecules often have short blood circulation times (half-life, t1/2, of hours), rely on a single high-affinity contact to a disease target, and are typically incapable of disrupting protein–protein interactions that can drive disease pathogenesis. In contrast, nano­scale systems can provide long circulation half-lives (days to weeks), have tunable valency and aqueous solubility, and are adept at preventing protein–protein interactions.2, 3 However, a significant advantage of small-molecule drugs is the ease with which large chemical and structural diversity can be manufactured and screened for biological activity. Synthetic routes to the creation of diversity in nanoparticle composition space would serve to combine many of the advantages of both small-molecule and nanoscale therapeutics. A number of materials have been explored as scaffolds for the design of nanometer-scale therapeutics. Notable recent examples are the pyrimadine-coated gold nanoparticle antibiotics studied by the Zhang laboratory4 and the dextran-coated iron oxide nanoparticles synthesized in Weissleder's laboratory.5, 6 The former experiments suggest that nanoparticles may be able to withstand pathogen evolutionary resistance mechanisms that plague small-molecule drugs, while the latter highlighted the remarkable ability of multivalent binding to strengthen drug-target binding interactions. Our laboratories have focused on gold nanoparticles as a platform for the discovery of novel therapeutics for the treatment of infectious disease. We chose gold for a number of reasons, including the ability to access gold nanoparticles in a range of well-defined sizes from 1 to 10 nm7, 8 and the straightforward gold modification chemistry afforded via formation of gold–thiolate bonds.9-11 In addition, using thiol exchange reactions, combinations of two or more chemically distinct organothiol ligands can be attached to a single particle to create multivalent and multifunctional systems.12 The ability to assemble mixed thiol monolayers on a nanoscale platform provides a powerful tool that can be used to tune binding affinity to a biological target and control cellular internalization and subcellular localization.13, 14 The potential benefits of gold nanoparticle therapeutics were demonstrated recently in our research groups by transforming a weak CCR5 binding small molecule, which by itself was biologically inactive, into a multivalent gold conjugate that effectively inhibited HIV-1 fusion to peripheral blood mononuclear cells (PBMCs) in vitro.15 The biological activity of ligand-coated gold nanoparticles in the prevention of HIV-1 entry suggests that known, weak binding or perhaps even resistance-compromised small-molecule drugs may be transformed into potent therapeutics via conjugation to gold nanoparticles. We were also interested in determining whether completely new biologically active compounds could be discovered using ligand-coated gold nanoparticles. Specifically, could we identify nanoparticle formulations whose biological activity was dictated by a specific combination of ligands displayed on the surface of the particle? Indeed the answer appears to be yes, as we have found that gold nanoparticles with potent activity for Escherichia coli (E. coli) growth inhibition could be discovered from a library of mixed thiol-monolayer-coated gold nanoparticles.16 Here, we show that the gold nanoparticle library created to search for inhibitors of the Gram-negative E. coli could be used to discover inhibitors of the Gram-positive bacterium Staphylococcus aureus (S. aureus). The active nanoparticles that emerged from this screen consisted of a different subset of the library compared to those discovered in the previous search. This suggests that the display of ligand mixtures on gold nanoparticles could present new opportunities in the rapid identification of nanomaterials with biological activity toward a range of microbes. The library of nanoparticle conjugates was assembled by first synthesizing 2.0 nm diameter gold nanoparticles capped with p-mercaptobenzoic acid (pMBA).15, 16 These particles have a proposed empirical formula of [Au144(SC6H4COOH)60].17 The ten thiols shown in Figure 1 were chosen as a representative library of molecules containing H-bond donor/acceptor and hydrophilic/hydrophobic properties. These ligands were incubated with gold nanoparticles in combinations of three (initially at 1:1:1 molar ratios) to build a library of 120 nanoparticle conjugates. The conjugates were purified by salt and methanol precipitation to remove free thiols. A large subset of these formulations (62 combinations) displayed poor aqueous solubility under the equimolar ligand exchange concentrations used initially. This was rectified by simply adjusting the molar ratio of thiols added into the reaction mixture. For example, nanoparticle conjugates 28 and 50 were relatively insoluble in aqueous solution due to the low solubility of thiol 1 (see structure in Figure 1). The amount of thiol 1 in the exchange reaction was thus reduced to 67% of the original feed. With the exchange reaction optimized for solubility, a total of 95 nanoparticle conjugates could be screened for antibiotic activity (see Supporting Information, Table S1 for the composition of the entire library). An initial screen against methicillin- susceptible S. aureus (MSSA) revealed activity that depended upon the combination of thiols conjugated to pMBA-coated gold nanoparticles (Figure 2). The ten thiols chosen as a representative library of molecules containing H-bond donor/acceptor and hydrophilic/hydrophobic properties. Antibiotic activity of several mixed ligand-coated gold nanoparticles. In parentheses are the thiols combined to generate each nanoparticle. Nanoparticle concentrations were 25 μM. POS indicates the positive control, and CFU indicates the colony forming unit. Nanoparticle conjugates that showed >90% growth inhibition at nanoparticle concentrations of 25 μM in the initial screen were chosen for further analysis. Cultures of MSSA were incubated with varying concentrations (10–50 μM) of nanoparticles. Assays were conducted under standard broth dilution procedures followed by colony counting to assess bacterial viability after incubation with nanoparticles. The nanoparticles shown in Table 1 displayed the highest decrease in growth, with conjugate 6 yielding 99.9% growth inhibition at 10 μM. The nanoparticles listed in Table 1 were then tested for activity against methicillin-resistant S. aureus (MRSA) and the Gram-negative bacterium E. coli. This screen allowed us to assess whether nanoparticle formulations could be discovered that were not susceptible to current mechanisms of drug resistance and whether nanoparticle formulations were also active against Gram-negative bacteria. All conjugates were as active against MRSA as they were toward MSSA except conjugate 56, which showed only 99.0% growth inhibition at 50 μM. None of the conjugates were active toward the inhibition of E. coli. The inhibitory activities of the individual, unconjugated thiols were then determined. Thiols 2, 5, 6, 8, 9, and 10 showed little to no inhibition of MSSA growth at concentrations as high as 2 mM (<0.4 log decrease). Thiols 3 and 4 were potent growth inhibitors, which is not surprising since phenols and anilines are known antiseptics. It was also found that thiol 7 showed inhibitory activity of ca. 1 log at 2 mM. However, for this thiol alone to be responsible for the activity of nanoparticles 50 and 56 it would require that more than 100 of them were coordinated to the gold surface, an unlikely scenario given that these nanoparticles can only accommodate 60 ligands total. Thiol 1 could not be screened in solution due to poor solubility in the broth used. However, on agar containing 500 μM 1 and 10% dimethyl sulfoxide (DMSO), no inhibition was observed. Various combinations of the free thiol monomers were then incubated with MSSA. Surprisingly, binary mixtures of 50 μM pMBA and 50 μM thiol 1 or 150 μM pMBA and 150 μM thiol 2 showed 99.9% MSSA growth inhibition. The activity of conjugates containing pMBA and thiols 1 or 2 is thus independent of their attachment to the nanoparticle; however, conjugation of 1 to the nanoparticle has the advantage of converting it into a water-soluble conjugate. Once we had identified active nanoparticle formulations, we employed IR spectroscopy to confirm the presence of thiols on conjugates 6, 28, and 50 (Figure 3). Characteristic vibrations for thiols 1 and 8 were observed for conjugate 6, and thiols 1 and 5 for conjugates 28 and 50. Thiols 2, 8, and 7 were not detected in conjugates 6, 28, and 50, respectively, likely because they were not present in sufficient quantities to be detected by IR or did not have vibrations that could be assigned unambiguously given the other thiols present. IR spectra of active nanoparticle conjugates 6, 28, and 50 confirms the formation of mixed thiol monolayers. A–D) Spectra of nanoparticle conjugates 6, 50, 28, and pMBA-gold nanoparticles, respectively. The * indicates a representative band for pMBA–Au nanoparticle conjugates. The ^, §, and £ correspond to vibrations unique to 3-(nitrobenzyl)mercaptan, glutathione, and 3-mercapto-1-propane sulfonate, respectively, as determined from the spectra of the free thiols. Finally, the toxicity of conjugate 50A was assessed with a hemolysis assay, yielding an HC50 of 40 μM. This value corresponds to a hemolytic index (HC50/MIC99.9) of 2 where HC50 is the concentration capable of causing 50% red blood cell lysis and MIC99.9 is the minimal inhibitory concentration resulting in 99.9% growth inhibition of S. aureus. Nanoscale systems including DNA aptamers, antibodies, proteins, and inorganic nanoparticles such as the gold particles described herein are attractive as therapeutics in part because of their tunable valencies, blood circulation times, and biodistribution profiles. In addition, nanoscale therapeutics are often adept at disrupting protein–protein interactions that can drive disease pathogenesis. In contrast, small-molecule therapeutics typically rely on a single high-affinity contact to a disease target and have difficulty blocking protein–protein interactions. A significant advantage of small-molecule drugs, however, is the ease with which large chemical and structural diversity can be manufactured and screened for biological activity. It has thus been proposed that methods capable of blending the properties of nanoscale systems with the chemical diversity of small molecules will lead to the discovery of superior therapeutic agents.1 We have shown that a library of small-molecule ligand-coated gold nanoparticle conjugates may be generated rapidly via one-pot thiol exchange reactions. The nanoparticle conjugates are prepared at room temperature in aqueous solution and purified using a simple aqueous salt/methanol precipitation and resuspension procedure. Considering solely the number of commercially available thiols (>200), there is potential to access significant chemical and structural diversity with this approach. While the aqueous solubility of the resulting nanoparticle conjugates may in some cases be low (as experienced with many of the compounds in our initial 120-member library), this can be overcome by simply tuning the molar ratios of the ligands during the exchange reaction or by combining thiols with low aqueous solubility with highly water-soluble thiols. The library of 95 unique ligand-coated gold nanoparticles investigated here revealed differential activity toward the inhibition of bacterial growth, with one conjugate displaying 99.9% growth inhibition at 10 μM for both MSSA and MRSA. Whether the bacterial growth inhibition observed for these conjugates is due to efficient internalization, nanoparticle aggregation inside of the cells, or enhanced binding to a biomolecule target located in the cell membrane or inside of the cell is currently not known. As a comparison we note that the minimum inhibitory concentrations of vancomycin, ciprofloxacin, and cefixime against MSSA are ca. 0.7, 1.5, and 17 mM, respectively; thus nanoparticle formulations can be rapidly identified from simple thiol building blocks that are comparable to conventional antibiotics with respect to in vitro bacterial growth inhibition. Synthesis of 2.0 nm Gold Nanoparticles: Two-nanometer dia­meter [Au144(SC6H4COOH)60] gold nanoparticles were synthesized as previously described.1 In short, a solution of HAuCl4 (11.1 mM), pMBA (37.8 mM), and NaOH (180 mM) in aqueous methanol (55.6% (v/v)) was prepared and allowed to equilibrate for 24 h with constant stirring. Fifty milliliters of this solution were diluted with the addition of methanol (260 mL) and water (740 mL). The Au+ was reduced with the addition of aqueous NaBH4 (10 mL, 0.25 M). The final methanol concentration was adjusted to 25% with the addition of water (100 mL). The reduction of gold was allowed to proceed for 48 h at room temperature with constant stirring. Gold nanoparticles were precipitated with the addition of NaCl (70 mmol) and methanol (500 mL) (final methanol concentration of 47% v/v) followed by centrifugation (3200 rcf, 5 min). The precipitated nanoparticles were reconstituted in water. The concentration was measured by UV–vis spectroscopy, using the molar extinction coefficient at a wavelength of 510 nm, ϵ510 nm, of 409 440 M−1 cm−1. Place Exchange Reactions: One-pot place exchange reactions were conducted with the addition of thiol added in 1:1:1 molar ratio (740 μM total) to gold nanoparticles (7.4 μM) in sodium phosphate buffer, pH 9.5 (20 mM, 15 mL). These solutions were prepared from 20 mM stock solutions of the individual thiols. Thiols 5, 6, 7, 8, 9, and 10 stock solutions were prepared in H2O, while thiols 1, 3, and 4 were dissolved in DMSO, and thiol 2 was dissolved in 20% glycerol. It is important to note that stock solutions of thiol 1 had to be be stored at –80 °C to avoid conversion into a species that fails to place exchange properly onto pMBA-capped gold nanoparticles. Reactions were placed on a plate shaker and agitated for 24 h at room temperature. The exchange product was harvested through the addition of NaCl (11 mL of 4 M stock for a final concentration of 0.8 M) and a volume of methanol equal to that of the reaction volume plus added salt water (26 mL). Reactions were centrifuged (3200 rcf, 30–60 min). Precipitated nanoparticles were resuspended and precipitated with the addition of NaCl and methanol two times to wash out excess unreacted thiol. Particles were allowed to dry to completion overnight at room temperature and resuspended in water. Resuspended nanoparticles were washed with water over a 30 000 MWCO (mole­cular weight cut-off) centricon filter to remove excess salt and thiol followed by buffer exchange into Mueller–Hinton broth for assay. Optimizing the molar feed ratios resulted in decreasing the concentration of thiols 1, 2, 3, 4, 6, 9, and 10 by 67% of the original value, with the rest of the reaction remaining as described above. The initial screen suggested that thiol 5 (glutathione) was an important ligand in the preparation of gold nanoparticle conjugates with activity toward MSSA. It was thus of interest to determine whether activity could be enhanced by starting with glutathione-capped gold nanoparticles rather than pMBA-capped gold nanoparticles. Glutathione-capped gold nanoparticles were synthesized by mixing HAuCl4•xH2O (0.4 mmol) in methanol (20 mL) with glutathione (1.4 mmol) in H2O (15.4 mL) supplemented with NaOH (0.6 mL of 10 M stock solution). This solution was then divided into thirds. The following was then added to each reaction: methanol (62 mL) and H2O (178 mL), followed by aqueous NaBH4 (2.4 mL, 0.25 M), and finally water (24 mL). Purification of the particles was performed via precipitation of nanoparticles with the addition of NaCl (40 mmol) and methanol (250 mL). Centrifugation of samples allowed for the purification of particles from the solution. Particles were then dissolved in water and washed over a 10 000 MWCO centricon filter to remove excess glutathione and salts. Place exchange reactions were then conducted on these particles as described above. Nanoparticles prepared in this way were designated conjugate 50A. Generation of nanoparticle conjugate 50A occurred through the addition of pMBA (2.95 μmol) and (3-nitrobenzyl)mercaptan (2.95 μmol) to glutathione-capped gold nanoparticles (0.05 μmol) in water (4 mL). These particles did not show enhanced activity versus conjugates prepared with pMBA-capped gold nanoparticles, although batch-to-batch variability was observed to improve. Bacterial Growth Inhibition Assays: Inoculation of S. aureus into Mueller–Hinton broth (3 mL, BD) was carried out by touching the top of 4 well-isolated colonies of MSSA (ATCC 29213), MRSA (ATCC BAA-44), or E. coli (ATCC 25922) from a Mueller–Hinton agar (BD) plate with an inoculation loop. The culture was allowed to grow at 37 °C, 225 rpm until mid-log phase after which it was diluted to 1 × 106 CFU/mL in Mueller–Hinton broth. Equal volumes of diluted inoculum and nanoparticle sample (adjusted to the correct assay concentration in Mueller–Hinton broth) were mixed to make the final inoculum concentration 5 × 105 CFU/mL. Samples were incubated at 37 °C, 225 rpm for 18 h. End points were determined by colony counting on Mueller–Hinton agar after dilution of each sample in phosphate buffered saline (PBS) and incubation of the plates at 37 °C for 24 h. Initial assays were conducted in nutrient broth and nutrient agar with S. aureus ATCC 9144, with final growth inhibition data documented for Mueller–Hinton broth and agar with S. aureus ATCC 29213. Infrared Spectroscopy: Nanoparticle samples were reconstituted and washed of contaminants over a 30 K MWCO centricon filter with water. Samples were then spotted onto potassium bromide Real Crystal IR cards (International Crystal Laboratories) in their appropriate solvent and allowed to dry. IR analysis was carried out on a Thermo Nicolet Avatar 360 FT-IR spectrometer. Blood Hemolysis Assay: Hemolysis assays were performed on mechanically difibrinated sheep's blood (Hemostat Labs: DSB100). Briefly, blood (1.5 mL) was placed into a microcentrifuge tube and centrifuged (10 000 rpm, 10 min). Cells were resuspended and washed with PBS (1 mL). The final cell suspension was then diluted tenfold and nanoparticle compound was added in PBS. PBS alone was used as a zero hemolysis marker and a 1% Triton X sample was used as a 100% lysis marker. Samples were then incubated at 37 °C, 200 rpm for 1 h followed by centrifugation (10 000 rpm, 10 min). The resulting supernatant was diluted by a factor of 40 in distilled water. The absorbance of the supernatant was measured with a UV–vis spectrometer at a 540 nm wavelength. As gold nanoparticles absorb readily at a 540 nm, the nanoparticles of each test sample were precipitated out of solution with NaCl and methanol. The resulting pellet was resuspended and the absorbance was measured with a UV–vis spectrometer at a 540 nm wavelength. This A540 nm reading represents nanoparticles and was subtracted from the initial A540 nm reading of the supernatant to yield A540 nm of cell lysis only. Supporting Information is available from the Wiley Online Library or from the author. The authors wish to thank the Bill and Melinda Gates Foundation for funding. The article is dedicated to Professor Chad Mirkin, a pioneering scientist and devoted mentor. This Communication is part of the Special Issue dedicated to Chad Mirkin in celebration of 20 years of influential research at Northwestern University. Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.}, number={14}, journal={SMALL}, author={Bresee, Jamee and Maier, Keith E. and Boncella, Amy E. and Melander, Christian and Feldheim, Daniel L.}, year={2011}, month={Jul}, pages={2027–2031} }
 @article{peng_desousa_su_novak_nevzorov_garland_melander_2011, title={Inhibition of Acinetobacter baumannii biofilm formation on a methacrylate polymer containing a 2-aminoimidazole subunit}, volume={47}, number={17}, journal={Chemical Communications (Cambridge, England)}, author={Peng, L. L. and DeSousa, J. and Su, Z. M. and Novak, B. M. and Nevzorov, A. A. and Garland, E. R. and Melander, C.}, year={2011}, pages={4896–4898} }
 @article{bunders_minvielle_worthington_ortiz_cavanagh_melander_2011, title={Intercepting Bacterial Indole Signaling with Flustramine Derivatives}, volume={133}, ISSN={["1520-5126"]}, DOI={10.1021/ja209836z}, abstractNote={Indole signaling is one of the putative universal signaling networks in bacteria. We have investigated the use of desformylflustrabromine (dFBr) derivatives for the inhibition of biofilm formation through modulation of the indole-signaling network in Escherichia coli and Staphylococcus aureus . We have found dFBr derivatives that are 10-1000 times more active than indole itself, demonstrating that the flustramine family of indolic natural products represent a privileged scaffold for the design of molecules to control pathogenic bacterial behavior.}, number={50}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Bunders, Cynthia A. and Minvielle, Marine J. and Worthington, Roberta J. and Ortiz, Minoshka and Cavanagh, John and Melander, Christian}, year={2011}, month={Dec}, pages={20160–20163} }
 @article{rogers_lindsey_whitehead_mullikin_melander_2011, title={Synthesis and biological evaluation of 2-aminoimidazole/carbamate hybrid anti-biofilm and anti-microbial agents}, volume={21}, ISSN={["1464-3405"]}, DOI={10.1016/j.bmcl.2010.12.057}, abstractNote={The successful marriage of structural features from our 2-aminoimidazole and menthyl carbamate classes of anti-biofilm agents has resulted in the development of a novel hybrid scaffold of biofilm modulators. The compounds were evaluated against a panel of four bacterial strains for anti-biofilm and anti-microbial activity.}, number={4}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Rogers, Steven A. and Lindsey, Erick A. and Whitehead, Daniel C. and Mullikin, Trey and Melander, Christian}, year={2011}, month={Feb}, pages={1257–1260} }
 @article{su_rogers_mccall_smith_ravishankar_mullikin_melander_2010, title={A nitroenolate approach to the synthesis of 4,5-disubstituted-2-aminoimidazoles. Pilot library assembly and screening for antibiotic and antibiofilm activity}, volume={8}, number={12}, journal={Organic & Biomolecular Chemistry}, author={Su, Z. M. and Rogers, S. A. and McCall, W. S. and Smith, A. C. and Ravishankar, S. and Mullikin, T. and Melander, C.}, year={2010}, pages={2814–2822} }
 @article{heinecke_melander_2010, title={Analysis of kinamycin D-mediated DNA cleavage}, volume={51}, ISSN={["0040-4039"]}, DOI={10.1016/j.tetlet.2009.12.142}, abstractNote={Kinamycin D is a potent antitumor antibiotic; however the biological mode of action is poorly understood. Recent efforts suggest the natural product is capable of generating reactive oxygen species under acidic pH to induce DNA damage in the presence of a reducing agent.}, number={11}, journal={TETRAHEDRON LETTERS}, author={Heinecke, Christine L. and Melander, Christian}, year={2010}, month={Mar}, pages={1455–1458} }
 @article{rogers_bero_melander_2010, title={Chemical Synthesis and Biological Screening of 2-Aminoimidazole-Based Bacterial and Fungal Antibiofilm Agents}, volume={11}, ISSN={["1439-7633"]}, DOI={10.1002/cbic.200900617}, abstractNote={Abstract}, number={3}, journal={CHEMBIOCHEM}, author={Rogers, Steven A. and Bero, Joseph D. and Melander, Christian}, year={2010}, month={Feb}, pages={396–410} }
 @article{bresee_maier_melander_feldheim_2010, title={Identification of antibiotics using small molecule variable ligand display on gold nanoparticles}, volume={46}, number={40}, journal={Chemical Communications (Cambridge, England)}, author={Bresee, J. and Maier, K. E. and Melander, C. and Feldheim, D. L.}, year={2010}, pages={7516–7518} }
 @article{bunders_richards_melander_2010, title={Identification of aryl 2-aminoimidazoles as biofilm inhibitors in Gram-negative bacteria}, volume={20}, ISSN={["0960-894X"]}, DOI={10.1016/j.bmcl.2010.04.042}, abstractNote={The synthesis and biofilm inhibitory activity of a 30-member aryl amide 2-aminoimidazole library against the three biofilm forming Gram-negative bacteria Escherichia coli, Psuedomonas aeruginosa, and Acinetobacter baumannii is presented. The most active compound identified inhibits the formation of E. coli biofilms with an IC50 of 5.2 μM and was observed to be non-toxic to planktonic growth, demonstrating that analogues based on an aryl framework are viable options as biofilm inhibitors within the 2-aminoimidazole family.}, number={12}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Bunders, Cynthia A. and Richards, Justin J. and Melander, Christian}, year={2010}, month={Jun}, pages={3797–3800} }
 @article{reed_huigens_rogers_melander_2010, title={Modulating the development of E. coli biofilms with 2-aminoimidazoles}, volume={20}, ISSN={["0960-894X"]}, DOI={10.1016/j.bmcl.2010.08.075}, abstractNote={The synthesis of a 20 member 2-aminoimidazole/triazole pilot library is reported. Each member of the library was screened for its ability to inhibit or promote biofilm development of either Escherichia coli and Acinetobacter baumannii. From this screen, E. coli-selective 2-aminoimidazoles were discovered, with the best inhibitor inhibiting biofilm development with an IC(50) of 13μM. The most potent promoter of E. coli biofilm formation promoted biofilm development by 321% at 400μM.}, number={21}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Reed, Catherine S. and Huigens, Robert W., III and Rogers, Steven A. and Melander, Christian}, year={2010}, month={Nov}, pages={6310–6312} }
 @article{rogers_huigens_cavanagh_melander_2010, title={Synergistic Effects between Conventional Antibiotics and 2-Aminoimidazole-Derived Antibiofilm Agents}, volume={54}, ISSN={["0066-4804"]}, DOI={10.1128/aac.01418-09}, abstractNote={ABSTRACT}, number={5}, journal={ANTIMICROBIAL AGENTS AND CHEMOTHERAPY}, author={Rogers, Steven A. and Huigens, Robert W., III and Cavanagh, John and Melander, Christian}, year={2010}, month={May}, pages={2112–2118} }
 @article{rogers_whitehead_mullikin_melander_2010, title={Synthesis and bacterial biofilm inhibition studies of ethyl N-(2-phenethyl) carbamate derivatives}, volume={8}, number={17}, journal={Organic & Biomolecular Chemistry}, author={Rogers, S. A. and Whitehead, D. C. and Mullikin, T. and Melander, C.}, year={2010}, pages={3857–3859} }
 @article{huigens_reyes_reed_bunders_rogers_steinhauer_melander_2010, title={The chemical synthesis and antibiotic activity of a diverse library of 2-aminobenzimidazole small molecules against MRSA and multidrug-resistant A. baumannii}, volume={18}, ISSN={["1464-3391"]}, DOI={10.1016/j.bmc.2009.12.003}, abstractNote={Multidrug-resistant bacterial infections continue to be a rising global health concern. Herein is described the development of a class of novel 2-aminobenzimidazoles with antibiotic activity. These active 2-aminobenzimidazoles retain their antibiotic activity against several strains of multidrug-resistant Staphylococcus aureus and Acinetobacter baumannii when compared to susceptible strains.}, number={2}, journal={BIOORGANIC & MEDICINAL CHEMISTRY}, author={Huigens, Robert W., III and Reyes, Samuel and Reed, Catherine S. and Bunders, Cynthia and Rogers, Steven A. and Steinhauer, Andrew T. and Melander, Christian}, year={2010}, month={Jan}, pages={663–674} }
 @article{rogers_huigens_melander_2009, title={A 2-Aminobenzimidazole That Inhibits and Disperses Gram-Positive Biofilms through a Zinc-Dependent Mechanism}, volume={131}, ISSN={["0002-7863"]}, DOI={10.1021/ja9024676}, abstractNote={A number of 2-aminobenzimidazole derivatives were synthesized and screened for their ability to inhibit and disperse bacterial biofilms. From these compounds, a lead 2-aminobenzimidazole was identified that both inhibited and dispersed MRSA, vancomycin-resistant Enterococcus faecium, and Staphylococcus epidermidis biofilms. Mechanistic studies showed that the activity is Zn(II)-dependent, potentially via a direct zinc-chelating mechanism.}, number={29}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Rogers, Steven A. and Huigens, Robert W., III and Melander, Christian}, year={2009}, month={Jul}, pages={9868-+} }
 @article{richards_reyes_stowe_tucker_ballard_mathies_cavanagh_melander_2009, title={Amide Isosteres of Oroidin: Assessment of Antibiofilm Activity and C. elegans Toxicity}, volume={52}, ISSN={["1520-4804"]}, DOI={10.1021/jm900378s}, abstractNote={The synthesis and antibiofilm activities of sulfonamide, urea, and thiourea oroidin analogues are described. The most active derivative was able to selectively inhibit P. aeruginosa biofilm development and is also shown to be nontoxic upward of 1 mM to the development of C. elegans in comparison to other similar isosteric analogues and the natural product oroidin.}, number={15}, journal={JOURNAL OF MEDICINAL CHEMISTRY}, author={Richards, Justin J. and Reyes, Samuel and Stowe, Sean D. and Tucker, Ashley T. and Ballard, T. Eric and Mathies, Laura D. and Cavanagh, John and Melander, Christian}, year={2009}, month={Aug}, pages={4582–4585} }
 @article{ballard_richards_aquino_reed_melander_2009, title={Antibiofilm Activity of a Diverse Oroidin Library Generated through Reductive Acylation}, volume={74}, ISSN={["0022-3263"]}, DOI={10.1021/jo802260t}, abstractNote={A diverse 20-compound library of analogues based on the marine alkaloid oroidin were synthesized via a reductive acylation strategy. The final target was then assayed for inhibition and dispersion activity against common proteobacteria known to form biofilms. This methodology represents a significant improvement over the generality of known methods to acylate substrates containing 2-aminoimidazoles and has the potential to have broad application to the synthesis of more advanced oroidin family members and their corresponding analogues.}, number={4}, journal={JOURNAL OF ORGANIC CHEMISTRY}, author={Ballard, T. Eric and Richards, Justin J. and Aquino, Arianexys and Reed, Catherine S. and Melander, Christian}, year={2009}, month={Feb}, pages={1755–1758} }
 @misc{richards_melander_2009, title={Controlling Bacterial Biofilms}, volume={10}, ISSN={["1439-7633"]}, DOI={10.1002/cbic.200900317}, abstractNote={The ubiquitous nature of bacteria in the environment, and the role they play in infectious disease has been one of the most extensively researched areas in biomedical science. It has led to tremendous scientific breakthroughs aimed at eradicating a myriad of diseases and improving the overall quality of life. However, within the past 20–30 years, there has been an ACHTUNGTRENNUNGincreased understanding that bacterial biofilms are a major factor in the morbidity and mortality of most infectious diseases. This is significant because bacterial biofilms are resistant to common therapeutic approaches that would eliminate their free-floating (planktonic) counterparts. Biofilms are described as surface-associated communities of microorganisms encased in a protective extracellular matrix. Approximately 80 % of the world’s microbial biomass resides in the biofilm state, and the National Institutes of Health (NIH) estimates that upwards of 75 % of microbial infections that occur in the human body are underpinned by the formation and persistence of biofilms. Common diseases associated with the formation of biofilms include lung infections of individuals who suffer from cystic fibrosis (CF), burn wound infections, otitis media, bacterial endocarditis, and tooth decay (Table 1). 6] Additionally, the}, number={14}, journal={CHEMBIOCHEM}, author={Richards, Justin J. and Melander, Christian}, year={2009}, month={Sep}, pages={2287–2294} }
 @article{melander_moeller_ballard_richards_huigens_cavanagh_2009, title={Evaluation of dihydrooroidin as an antifouling additive in marine paint}, volume={63}, ISSN={["0964-8305"]}, DOI={10.1016/j.ibiod.2008.08.009}, abstractNote={Methods used to deter biofouling of underwater structures and marine vessels present a serious environmental issue and are both problematic and costly for government and commercial marine vessels worldwide. Current antifouling methods include compounds that are toxic to aquatic wildlife and marine ecosystems. Dihydrooroidin (DHO) was shown to completely inhibit Halomonas pacifica biofilms at 100 μM in a static biofilm inhibition assay giving precedence for the inhibition of other marine biofilm-forming organisms. Herein we present DHO as an effective paint-based, non-cytotoxic, antifouling agent against marine biofouling processes in a marine mesocosm.}, number={4}, journal={INTERNATIONAL BIODETERIORATION & BIODEGRADATION}, author={Melander, Christian and Moeller, Peter D. R. and Ballard, T. Eric and Richards, Justin J. and Huigens, Robert W., III and Cavanagh, John}, year={2009}, month={Jun}, pages={529–532} }
 @article{huigens_rogers_steinhauer_melander_2009, title={Inhibition of Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa biofilm formation with a class of TAGE-triazole conjugates}, volume={7}, ISSN={["1477-0539"]}, DOI={10.1039/b817926c}, abstractNote={A chemically diverse library of TAGE-triazole conjugates was synthesized utilizing click chemistry on the TAGE scaffold. This library of small molecules was screened for anti-biofilm activity and found to possess the ability of inhibiting biofilm formation against Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa. One such compound in this library demonstrated the most potent inhibitory effect against Staphylococcus aureus biofilm formation that has been displayed by any 2-aminoimidazole derivative.}, number={4}, journal={ORGANIC & BIOMOLECULAR CHEMISTRY}, author={Huigens, Robert W., III and Rogers, Steven A. and Steinhauer, Andrew T. and Melander, Christian}, year={2009}, pages={794–802} }
 @article{rogers_krayer_lindsey_melander_2009, title={Tandem dispersion and killing of bacteria from a biofilm}, volume={7}, ISSN={["1477-0539"]}, DOI={10.1039/b817923a}, abstractNote={The combined effects of biofilm dispersion with a 2-aminoimidazole-triazole conjugate and bactericidal activity with a photodynamic inactivation agent suggest a novel combination therapy for treating diverse microbial infections.}, number={3}, journal={ORGANIC & BIOMOLECULAR CHEMISTRY}, author={Rogers, Steven A. and Krayer, Michael and Lindsey, Jonathan S. and Melander, Christian}, year={2009}, pages={603–606} }
 @article{rogers_melander_2008, title={Construction and screening of a 2-aminoimidazole library identifies a small molecule capable of inhibiting and dispersing bacterial biofilms across order, class, and phylum}, volume={47}, ISSN={["1521-3773"]}, DOI={10.1002/anie.200800862}, abstractNote={Bacterial biofilms are defined as a surface-attached community of bacteria that are surrounded by a protective extracellular matrix. Within the biofilm state, bacteria display differential gene expression and are at least 1000-fold more resistant to antibiotic treatment. Biofilms account for more than 80% of all bacterial infections; they drive persistent infection of indwelling medical devices, and are responsible for the mortality and morbidity of almost all cystic fibrosis (CF) patients. Given the biomedical prominence of biofilms, there have been significant efforts to discover small molecules that modulate biofilm development. We have shown that simple derivatives of themarine natural product bromoageliferin will both inhibit and disperse bacterial biofilms (Scheme 1). Recently, we demonstrated that dihydrosventrin (DHS) inhibits and disperses Pseudomonas aeruginosa (multiple strains), Acinetobacter baumannii, and Bordetella bronchiseptica biofilms, making it the first small molecule reported to inhibit and disperse biofilms across bacterial order and class through a nonbactericidal mechanism. We have begun to investigate whether modifications to the core DHS structure will lead to derivatives with enhanced anti-biofilm activities. One of the first structural variations we have studied is replacement of the pyrrole subunit with a triazole subunit (Scheme 2). Herein we detail the develop-}, number={28}, journal={ANGEWANDTE CHEMIE-INTERNATIONAL EDITION}, author={Rogers, Steven A. and Melander, Christian}, year={2008}, pages={5229–5231} }
 @article{huigens_ma_gambino_moeller_basso_cavanagh_wozniak_melander_2008, title={Control of bacterial biofilms with marine alkaloid derivatives}, volume={4}, ISSN={["1742-2051"]}, DOI={10.1039/b719989a}, abstractNote={Bacterial biofilms are defined as a community of surface-attached bacteria that are protected by an extracellular matrix of biomolecules. We have recently reported the synthesis of a small molecule, denoted TAGE, based on the natural product bromoageliferin and demonstrated that TAGE has anti-biofilm activity against Pseudomonas aeruginosa. Herein we demonstrate that TAGE: (1) does not have selective toxicity against cells within the biofilm state, (2) will inhibit biofilm development under flow conditions, indicating that the CV staining protocol correlates with the ability to be active under biomimetic conditions, and (3) will disperse preformed P. aeruginosa biofilms. We also present preliminary toxicity work that indicates that TAGE is devoid of cytotoxicity in rat and mice cell lines. Advanced derivatives of TAGE have generated compounds shown to be exceedingly effective as biofilm inhibitors against the gamma-proteobacteria in this study (P. aeruginosa strains PAO1, PA14, PDO300, and Acinetobacter baumannii). TAGE derivatives also possessed anti-biofilm activity against the beta-proteobacterium Bordetella bronchiseptica (Rb50) and the Gram-positive bacterium Staphylococcus aureus;TAGE derivatives inhibited the formation of biofilms, however, some of this activity is attributed to microbicidal activity. The TAGE derivatives presented in this study, however, do not disperse pre-formed biofilms with the same efficiency as TAGE.}, number={6}, journal={MOLECULAR BIOSYSTEMS}, author={Huigens, Robert W., III and Ma, Luyan and Gambino, Christopher and Moeller, Peter D. R. and Basso, Anne and Cavanagh, John and Wozniak, Daniel J. and Melander, Christian}, year={2008}, pages={614–621} }
 @article{richards_reed_melander_2008, title={Effects of N-pyrrole substitution on the anti-biofilm activities of oroidin derivatives against Acinetobacter baumannii}, volume={18}, ISSN={["0960-894X"]}, DOI={10.1016/j.bmcl.2008.06.089}, abstractNote={Bacteria of the genus Acinetobacter spp. are rapidly emerging as problematic pathogens in healthcare settings. This is exacerbated by the bacteria’s ability to form robust biofilms. Marine natural products incorporating a 2-aminoimidazole (2-AI) motif, namely from the oroidin class of marine alkaloids, have served as a unique scaffold for developing molecules that have the ability to inhibit and disperse bacterial biofilms. Herein we present the anti-biofilm activity of a small library of second generation oroidin analogues against the bacterium Acinetobacter baumannii.}, number={15}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Richards, Justin J. and Reed, Catherine S. and Melander, Christian}, year={2008}, month={Aug}, pages={4325–4327} }
 @article{richards_ballard_melander_2008, title={Inhibition and dispersion of Pseudomonas aeruginosa biofilms with reverse amide 2-aminoimidazole oroidin analogues}, volume={6}, ISSN={["1477-0539"]}, DOI={10.1039/b719082d}, abstractNote={The marine alkaloid oroidin along with a small library of reverse amide (RA) 2-aminoimidazoles were synthesized and assayed for anti-biofilm activity against PAO1 and PA14, two strains of the medically relevant gamma-proteobacterium Pseudomonas aeruginosa. Analogues that contained a long, linear alkyl chain were more potent inhibitors than the natural product at preventing the formation of PAO1 and PA14 biofilms. The most active compound in the series was also shown to disperse established PAO1 and PA14 biofilms at low micromolar concentrations.}, number={8}, journal={ORGANIC & BIOMOLECULAR CHEMISTRY}, author={Richards, Justin J. and Ballard, T. Eric and Melander, Christian}, year={2008}, pages={1356–1363} }
 @article{richards_huigens_ballard_basso_cavanagh_melander_2008, title={Inhibition and dispersion of proteobacterial biofilms}, number={14}, journal={Chemical Communications (Cambridge, England)}, author={Richards, J. J. and Huigens, R. W. and Ballard, T. E. and Basso, A. and Cavanagh, J. and Melander, C.}, year={2008}, pages={1698–1700} }
 @article{bowman_ballard_ackerson_feldheim_margolis_melander_2008, title={Inhibition of HIV fusion with multivalent gold nanoparticles}, volume={130}, ISSN={["0002-7863"]}, DOI={10.1021/ja710321g}, abstractNote={The design and synthesis of a multivalent gold nanoparticle therapeutic is presented. SDC-1721, a fragment of the potent HIV inhibitor TAK-779, was synthesized and conjugated to 2.0 nm diameter gold nanoparticles. Free SDC-1721 had no inhibitory effect on HIV infection; however, the (SDC-1721)-gold nanoparticle conjugates displayed activity comparable to that of TAK-779. This result suggests that multivalent presentation of small molecules on gold nanoparticle surfaces can convert inactive drugs into potent therapeutics.}, number={22}, journal={JOURNAL OF THE AMERICAN CHEMICAL SOCIETY}, author={Bowman, Mary-Catherine and Ballard, T. Eric and Ackerson, Christopher J. and Feldheim, Daniel L. and Margolis, David M. and Melander, Christian}, year={2008}, month={Jun}, pages={6896-+} }
 @article{ballard_melander_2008, title={Kinamycin-mediated DNA cleavage under biomimetic conditions}, volume={49}, ISSN={["0040-4039"]}, DOI={10.1016/j.tetlet.2008.03.019}, abstractNote={The kinamycins are biologically active secondary metabolites characterized by an uncommon diazobenzo[b]fluorene skeleton. Kinamycin D has been shown to potently cleave DNA under mild biomimetic conditions. Use of the endogenously abundant reductant glutathione at 570 μM, kinamycin D effectively cleaved DNA in a concentration, temperature, and time-dependent fashion. Dithiothreitol also proved effective at low concentration while other reductants failed to induce DNA cleavage. Mechanistic consequences of the DNA cleavage results are described.}, number={19}, journal={TETRAHEDRON LETTERS}, author={Ballard, T. Eric and Melander, Christian}, year={2008}, month={May}, pages={3157–3161} }
 @article{ballard_richards_wolfe_melander_2008, title={Synthesis and Antibiofilm Activity of a Second-Generation Reverse-Amide Oroidin Library: A Structure-Activity Relationship Study}, volume={14}, ISSN={["1521-3765"]}, DOI={10.1002/chem.200801419}, abstractNote={Abstract}, number={34}, journal={CHEMISTRY-A EUROPEAN JOURNAL}, author={Ballard, T. Eric and Richards, Justin J. and Wolfe, Amanda L. and Melander, Christian}, year={2008}, pages={10745–10761} }
 @article{richards_ballard_huigens_melander_2008, title={Synthesis and screening of an oroidin library against Pseudomonas aeruginosa biofilms}, volume={9}, ISSN={["1439-4227"]}, DOI={10.1002/cbic.200700774}, abstractNote={Abstract}, number={8}, journal={CHEMBIOCHEM}, author={Richards, Justin J. and Ballard, T. Eric and Huigens, Robert W., III and Melander, Christian}, year={2008}, month={May}, pages={1267–1279} }
 @article{richards_melander_2008, title={Synthesis of a 2-aminoimidazole library for antibiofilm screening utilizing the Sonogashira reaction}, volume={73}, ISSN={["0022-3263"]}, DOI={10.1021/jo800618q}, abstractNote={The divergent synthesis of a 21-member library composed of 2-aminoimidazole compounds for evaluation as novel antibiofilm molecules is presented. The Sonogashira reaction was employed with three regioisomeric aryl iodides and 11 different alkynes to generate variously substituted diverse ring systems. Good to excellent yields (80-97%) for the reaction were obtained, and the products provide adequate handles for further manipulation into more advanced analogues.}, number={13}, journal={JOURNAL OF ORGANIC CHEMISTRY}, author={Richards, Justin J. and Melander, Christian}, year={2008}, month={Jul}, pages={5191–5193} }
 @article{burns_bobay_basso_cavanagh_melander_2008, title={Targeting RNA with cysteine-constrained peptides}, volume={18}, ISSN={["0960-894X"]}, DOI={10.1016/j.bmcl.2007.11.096}, abstractNote={A combined approach for targeting RNA with novel, biologically active ligands has been developed using a cyclic peptide library and in silico modeling. This approach has successfully identified novel cyclic peptide constructs that can target bTAR RNA. Subsequently, RNA/peptide interactions were effectively modeled using the HADDOCK docking program.}, number={2}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Burns, Virginia A. and Bobay, Benjamin G. and Basso, Anne and Cavanagh, John and Melander, Christian}, year={2008}, month={Jan}, pages={565–567} }
 @article{huigens_richards_parise_ballard_zeng_deora_melander_2007, title={Inhibition of Pseudomonas aeruginosa biofilm formation with bromoageliferin analogues}, volume={129}, number={22}, journal={Journal of the American Chemical Society}, author={Huigens, R. W. and Richards, J. J. and Parise, G. and Ballard, T. E. and Zeng, W. and Deora, R. and Melander, C.}, year={2007}, pages={6966-} }
 @article{zeng_ballard_tkachenko_burns_feldheim_melander_2006, title={Mimicking the biological activity of diazobenzo[b]fluorene natural products with electronically tuned diazofluorene analogs}, volume={16}, ISSN={["0960-894X"]}, DOI={10.1016/j.bmcl.2006.07.024}, abstractNote={Under appropriate electronic modulation, simple diazofluorene analogs recapitulate the DNA cleavage activity of kinamycin D under thiol-based reducing conditions. Achieving DNA cleavage under these reducing conditions is key to anticancer activity, as the most active compound, 1-methoxydiazofluorene, inhibits the proliferation of HeLa cells.}, number={19}, journal={BIOORGANIC & MEDICINAL CHEMISTRY LETTERS}, author={Zeng, Wei and Ballard, T. Eric and Tkachenko, Alexander G. and Burns, Virginia A. and Feldheim, Daniel L. and Melander, Christian}, year={2006}, month={Oct}, pages={5148–5151} }
 @article{zeng_ballard_melander_2006, title={Tuning the oxidation properties of vanadium(V) through ligand stoichiometry}, volume={47}, ISSN={["0040-4039"]}, DOI={10.1016/j.tetlet.2006.06.051}, abstractNote={Vanadium(V) (5 mol %) and hydroxamic acid ligand (45 mol %) were found to promote the selective tert-butyl hydroperoxide-mediated oxidation of allylic and propargylic alcohols to the corresponding aldehydes and ketones.}, number={33}, journal={TETRAHEDRON LETTERS}, author={Zeng, Wei and Ballard, T. Eric and Melander, Christian}, year={2006}, month={Aug}, pages={5923–5926} }