@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={AbstractThere is an urgent need to develop new drugs against tuberculosis. In particular, it is critical to target drug tolerant Mycobacterium tuberculosis (M. tuberculosis), responsible, in part, for the lengthy antibiotic regimen required for treatment. We previously postulated that the presence of in vivo biofilm-like communities of M. tuberculosis could contribute to this drug tolerance. Consistent with this hypothesis, certain 2-aminoimidazole (2-AIs) molecules with anti-biofilm activity were shown to revert mycobacterial drug tolerance in an in vitro M. tuberculosis biofilm model. While exploring their mechanism of action, it was serendipitously observed that these 2-AI molecules also potentiated β-lactam antibiotics by affecting mycobacterial protein secretion and lipid export. As these two bacterial processes are energy-dependent, herein it was evaluated if 2-AI compounds affect mycobacterial bioenergetics. At low concentrations, 2B8, the lead 2-AI compound, collapsed both components of the proton motive force, similar to other cationic amphiphiles. Interestingly, however, the minimum inhibitory concentration of 2B8 against M. tuberculosis correlated with a higher drug concentration determined to interfere with the mycobacterial electron transport chain. Collectively, this study elucidates the mechanism of action of 2-AIs against M. tuberculosis, providing a tool to better understand mycobacterial bioenergetics and develop compounds with improved anti-mycobacterial activity.}, 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={AbstractTuberculosis (TB) remains a significant global health problem for which new therapeutic options are sorely needed. The ability of the causative agent, Mycobacterium tuberculosis, to reside within host macrophages and form biofilm‐like communities contributes to the persistent and drug‐tolerant nature of the disease. Compounds that can prevent or reverse the biofilm‐like phenotype have the potential to serve alongside TB antibiotics to overcome this tolerance, and decrease treatment duration. Using Mycobacterium smegmatis as a surrogate organism, we report the identification of two new 2‐aminoimidazole compounds that inhibit and disperse mycobacterial biofilms, work synergistically with isoniazid and rifampicin to eradicate preformed M. smegmatis biofilms in vitro, are nontoxic toward Galleria mellonella, and exhibit stability in mouse plasma.}, 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{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{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} }
 @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} }
 @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{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={SummaryWith antibiotic resistance increasing at alarming rates, targets for new antimicrobial therapies must be identified. A particularly promising target is the bacterial two‐component system. Two‐component systems allow bacteria to detect, evaluate and protect themselves against changes in the environment, such as exposure to antibiotics and also to trigger production of virulence factors. Drugs that target the response regulator portion of two‐component systems represent a potent new approach so far unexploited. Here, we focus efforts on the highly virulent bacterium Francisella tularensis tularensis. Francisella contains only three response regulators, making it an ideal system to study. In this study, we initially present the structure of the N‐terminal domain of QseB, the response regulator responsible for biofilm formation. Subsequently, using binding assays, computational docking and cellular studies, we show that QseB interacts with2‐aminoimidazole based compounds that impede its function. This information will assist in tailoring compounds to act as adjuvants that will enhance the effect of antibiotics.}, 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{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={AbstractA library of 2‐aminobenzimidazole derivatives was screened for the ability to suppress β‐lactam resistance in Mycobacterium smegmatis. Several non‐bactericidal compounds were identified that reversed intrinsic resistance to β‐lactam antibiotics in a manner distinct from β‐lactamase inhibitors. Activity also translates to M. tuberculosis, with a lead compound from this study potently suppressing carbenicillin resistance in multiple M. tuberculosis strains (including multidrug‐resistant strains). Preliminary mechanistic studies revealed that the lead compounds act through a mechanism distinct from that of traditional β‐lactamase inhibitors.}, 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{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{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{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{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{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{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{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={Herein, we report azo-benzimidazole containing cobalt complexes (1–3) for alcohol dehydrogenation-triggered C3-alkylation of indoles. In complexes 1–3, ligands are redox noninnocent and showed facile irreversible L/L• reduction followed by Co­(II)/Co­(I) reduction in close-lying potentials. Taking advantage of facile redox events in 1–3, the first aerial dehydrogenation of alcohols to their corresponding carbonyl compounds is explored. Subsequently, C3-alkylation of indole was studied using alcohols as the alkylating agents. The developed catalytic protocol was found to be efficient and very selective. It has a broad substrate scope and good functional group tolerance. As far as we are aware, it is the first homogeneous cobalt catalyst for C3-alkylation of indole using alcohol as the alkylating agent. Detailed mechanistic studies, including a deuterium labeling experiment, have suggested a borrowing hydrogen method for the C3-alkylation of indole. The coordinated ligand, cooperatively with the Co­(II)/Co­(I) redox couple, oxidized the coordinated alkoxide in a radical pathway to result in the carbonyl compound (Scheme 1), which on subsequent condensation with indole generates the alkylideneindolenine intermediate "X". Reduction of "X" by an azo-anion radical Co­(I) catalyst intermediate resulted in the C3-alkylated indole.}, number={37}, journal={TETRAHEDRON}, author={Melander, Roberta J. and Minvielle, Marine J. and Melander, Christian}, year={2014}, month={Sep}, pages={6363–6372} }
 @article{wright_wu_melander_melander_lamont_2014, title={Disruption of heterotypic community development by Porphyromonas gingivalis with small molecule inhibitors}, volume={29}, ISSN={["2041-1014"]}, DOI={10.1111/omi.12060}, abstractNote={SummaryPorphyromonas gingivalis is one of the main etiological organisms in periodontal disease. On oral surfaces P. gingivalis is a component of multispecies biofilm communities and can modify the pathogenic potential of the community as a whole. Accumulation of P. gingivalis in communities is facilitated by interspecies binding and communication with the antecedent colonizer Streptococcus gordonii. In this study we screened a library of small molecules to identify structures that could serve as lead compounds for the development of inhibitors of P. gingivalis community development. Three small molecules were identified that effectively inhibited accumulation of P. gingivalis on a substratum of S. gordonii. The structures of the small molecules are derived from the marine alkaloids oroidin and bromoageliferin and contain a 2‐aminoimidazole or 2‐aminobenzimidazole moiety. The most active compounds reduced expression of mfa1 and fimA in P. gingivalis, genes encoding the minor and major fimbrial subunits, respectively. These fimbrial adhesins are necessary for P. gingivalis co‐adhesion with S. gordonii. These results demonstrate the potential for a small molecular inhibitor‐based approach to the prevention of diseases associated with P. gingivalis.}, number={5}, journal={MOLECULAR ORAL MICROBIOLOGY}, author={Wright, C. J. and Wu, H. and Melander, R. J. and Melander, C. and Lamont, J.}, year={2014}, month={Oct}, pages={185–193} }
 @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{melander_selwood_2015, title={Small Steps to New Drugs for Bugs}, volume={85}, ISSN={["1747-0285"]}, DOI={10.1111/cbdd.12482}, abstractNote={Governments, academics and industry are beginning to listen to the medical communities call for new anti‐bacterials. This special issue brings together diverse review articles on topics from economics and pricing to new discovery methods.}, number={1}, journal={CHEMICAL BIOLOGY & DRUG DESIGN}, author={Melander, Roberta J. and Selwood, David L.}, year={2015}, month={Jan}, pages={1–3} }
 @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{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{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{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} }
 @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{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{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{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{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{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} }
 @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={AbstractA library of 4,5‐disubstituted‐2‐aminoimidazole–triazole conjugates (2‐AITs) was synthesized, and the antibiofilm activity was investigated. This class of small molecules was found to inhibit biofilm formation by methicillin‐resistant Staphylococcus aureus (MRSA) at low‐micromolar concentrations; 4,5‐disubstituted‐2‐AITs were also able to inhibit and disperse Acinetobacter baumannii biofilms. The activities of the lead compounds were compared against the naturally occurring biofilm dispersant cis‐2‐decenoic acid and were revealed to be more potent. The ability of selected compounds to resensitize MRSA to traditional antibiotics (resensitization activity) was also determined. Lead compounds were observed to resensitize MRSA to oxacillin by 2–4‐fold.}, 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{gooding_tudzarova_worthington_kingsbury_rebstock_dube_simone_visintin_lagos_quesada_et al._2012, title={Exploring the Interaction Between siRNA and the SMoC Biomolecule Transporters: Implications for Small Molecule-Mediated Delivery of siRNA}, volume={79}, ISSN={["1747-0277"]}, DOI={10.1111/j.1747-0285.2011.01249.x}, abstractNote={The small molecule carrier class of biomolecule transporters, modeled on the third helix of the Antennapedia homeodomain, has previously been shown to transport active proteins into cells. Here, we show an improved synthetic route to small molecule carriers, including Molander chemistry using trifluoroborate salts to improve the yield of the Suzuki–Miyaura coupling step for the formation of the biphenyl backbone. The required boronic acids could be formed by the reaction of a 2‐(dimethylamino)ethyl ether‐modified aryl Grignard reagent with triisopropyl borate. The potential for the use of small molecule carriers as oligonucleotide‐transporting agents was also explored by characterizing the interactions between small molecule carriers and siRNA. Molecular dynamics and NMR analysis indicated that the small molecule carrier guanidines are stabilized by π‐cation interactions with the biphenyl system, thus not only increasing the basicity or pKa but also shielding the charge. The binding affinities of various small molecule carriers for siRNA were investigated using isothermal calorimetry and gel shift assays. Small molecule carrier‐mediated siRNA delivery to cultured fibroblasts is demonstrated, showing that small molecule carriers possess the ability to transport functional siRNA into cells. Knockdown of Cdc7 kinase, a target for cancer, is achieved.}, number={1}, journal={CHEMICAL BIOLOGY & DRUG DESIGN}, author={Gooding, Matt and Tudzarova, Slavica and Worthington, Roberta J. and Kingsbury, Sarah R. and Rebstock, Anne-Sophie and Dube, Henry and Simone, Michela I. and Visintin, Cristina and Lagos, Dimitris and Quesada, Juan-Manuel Funes and et al.}, year={2012}, month={Jan}, pages={9–21} }
 @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} }