@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{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{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} }