@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{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{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} }