Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli
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Author(s)
Opperman, Timothy J.
Kwasny, Steven M.
Kim, Hong-Suk
Nguyen, Son T.
Houseweart, Chad
D'Souza, Sanjay Victor
Walker, Graham C.
Peet, Norton P.
Nikaido, Hiroshi
Bowlin, Terry L.
Date Issued
November 2013
Journal
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Citation
Opperman, T. J., S. M. Kwasny, H.-S. Kim, S. T. Nguyen, C. Houseweart, S. D’Souza, G. C. Walker, N. P. Peet, H. Nikaido, and T. L. Bowlin. “Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia coli.” Antimicrobial Agents and Chemotherapy 58, no. 2 (November 18, 2013): 722–733.
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Author's final manuscript
Abstract
Members of the resistance-nodulation-division (RND) family of efflux pumps, such as AcrAB-TolC of Escherichia coli, play major roles in multidrug resistance (MDR) in Gram-negative bacteria. A strategy for combating MDR is to develop efflux pump inhibitors (EPIs) for use in combination with an antibacterial agent. Here, we describe MBX2319, a novel pyranopyridine EPI with potent activity against RND efflux pumps of the Enterobacteriaceae. MBX2319 decreased the MICs of ciprofloxacin (CIP), levofloxacin, and piperacillin versus E. coli AB1157 by 2-, 4-, and 8-fold, respectively, but did not exhibit antibacterial activity alone and was not active against AcrAB-TolC-deficient strains. MBX2319 (3.13 μM) in combination with 0.016 μg/ml CIP (minimally bactericidal) decreased the viability (CFU/ml) of E. coli AB1157 by 10,000-fold after 4 h of exposure, in comparison with 0.016 μg/ml CIP alone. In contrast, phenyl-arginine-β-naphthylamide (PAβN), a known EPI, did not increase the bactericidal activity of 0.016 μg/ml CIP at concentrations as high as 100 μM. MBX2319 increased intracellular accumulation of the fluorescent dye Hoechst 33342 in wild-type but not AcrAB-TolC-deficient strains and did not perturb the transmembrane proton gradient. MBX2319 was broadly active against Enterobacteriaceae species and Pseudomonas aeruginosa. MBX2319 is a potent EPI with possible utility as an adjunctive therapeutic agent for the treatment of infections caused by Gram-negative pathogens.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1128/aac.01866-13
