Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

Abdali, Narges; Parks, Jerry M.; Haynes, Keith M.; Chaney, Julie L.; Green, Adam T.; Wolloscheck, David; Walker, John K.; Rybenkov, Valentin V.; Baudry, Jerome; Smith, Jeremy C.; Zgurskaya, Helen I.

doi:10.1021/acsinfecdis.6b00167

Title: Reviving Antibiotics: Efflux Pump Inhibitors That Interact with AcrA, a Membrane Fusion Protein of the AcrAB-TolC Multidrug Efflux Pump

Journal Article · Fri Oct 21 00:00:00 EDT 2016 · ACS Infectious Diseases

DOI:https://doi.org/10.1021/acsinfecdis.6b00167· OSTI ID:1341559

Abdali, Narges ^[1]; Parks, Jerry M. ^[2]; Haynes, Keith M. ^[3]; Chaney, Julie L. ^[1]; Green, Adam T. ^[4]; Wolloscheck, David ^[1]; Walker, John K. ^[3]; Rybenkov, Valentin V. ^[1]; Baudry, Jerome ^[2]; Smith, Jeremy C. ^[2]; Zgurskaya, Helen I. ^[1]

Univ. of Oklahoma, Norman, OK (United States). Dept. of Chemistry and Biochemistry
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics; Univ. of Tennessee, Knoxville, TN (United States). Dept. of Biochemistry and Cellular and Molecular Biology
Saint Louis Univ. School of Medicine, MS (United States). Dept. of Pharmacological and Physiological Science
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics

Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump, change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1341559

Journal Information:: ACS Infectious Diseases, Vol. 3, Issue 1; ISSN 2373-8227

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 53 works

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Involvement of multiple influx and efflux transporters in the accumulation of cationic fluorescent dyes by Escherichia coli Jindal, Srijan; Yang, Lei; Day, Philip J. BMC Microbiology, Vol. 19, Issue 1 https://doi.org/10.1186/s12866-019-1561-0	journal	August 2019
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