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

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.
Authors:
 [1] ;  [2] ;  [3] ;  [1] ;  [4] ;  [1] ;  [3] ;  [1] ;  [2] ;  [2] ;  [1]
  1. Univ. of Oklahoma, Norman, OK (United States). Dept. of Chemistry and Biochemistry
  2. 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
  3. Saint Louis Univ. School of Medicine, MS (United States). Dept. of Pharmacological and Physiological Science
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Molecular Biophysics
Publication Date:
Grant/Contract Number:
AC05-00OR22725
Type:
Accepted Manuscript
Journal Name:
ACS Infectious Diseases
Additional Journal Information:
Journal Volume: 3; Journal Issue: 1; Journal ID: ISSN 2373-8227
Publisher:
American Chemical Society (ACS)
Research Org:
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Oak Ridge Leadership Computing Facility (OLCF)
Sponsoring Org:
USDOE Office of Science (SC)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Titan
OSTI Identifier:
1341559