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Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli.
Antimicrob Agents Chemother 2014; 58(2):722-33AA

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.

Authors+Show Affiliations

Microbiotix, Inc., Worcester, Massachusetts, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24247144

Citation

Opperman, Timothy J., et al. "Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia Coli." Antimicrobial Agents and Chemotherapy, vol. 58, no. 2, 2014, pp. 722-33.
Opperman TJ, Kwasny SM, Kim HS, et al. Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrob Agents Chemother. 2014;58(2):722-33.
Opperman, T. J., Kwasny, S. M., Kim, H. S., Nguyen, S. T., Houseweart, C., D'Souza, S., ... Bowlin, T. L. (2014). Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. Antimicrobial Agents and Chemotherapy, 58(2), pp. 722-33. doi:10.1128/AAC.01866-13.
Opperman TJ, et al. Characterization of a Novel Pyranopyridine Inhibitor of the AcrAB Efflux Pump of Escherichia Coli. Antimicrob Agents Chemother. 2014;58(2):722-33. PubMed PMID: 24247144.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of a novel pyranopyridine inhibitor of the AcrAB efflux pump of Escherichia coli. AU - Opperman,Timothy J, AU - Kwasny,Steven M, AU - Kim,Hong-Suk, AU - Nguyen,Son T, AU - Houseweart,Chad, AU - D'Souza,Sanjay, AU - Walker,Graham C, AU - Peet,Norton P, AU - Nikaido,Hiroshi, AU - Bowlin,Terry L, Y1 - 2013/11/18/ PY - 2013/11/20/entrez PY - 2013/11/20/pubmed PY - 2014/9/23/medline SP - 722 EP - 33 JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 58 IS - 2 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/24247144/Characterization_of_a_novel_pyranopyridine_inhibitor_of_the_AcrAB_efflux_pump_of_Escherichia_coli_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=24247144 DB - PRIME DP - Unbound Medicine ER -