Multidrug Efflux Pumps and the Two-Faced Janus of Substrates and Inhibitors
Abstract
Antibiotics are miracle drugs that can cure infectious bacterial diseases. However, their utility is challenged by antibiotic resistant bacteria emerging in clinics and straining the modern medicine and our ways of life. Certain bacteria such as Gram-negative (Gram(- )) and Mycobacteriales species are intrinsically resistant to most clinical antibiotics and can further gain multidrug resistance through mutations and plasmid acquisition. These species stand out by the presence of an additional external lipidic membranes (the outer membrane, OM) that are composed of unique glycolipids. Although formidable, the OM is a passive permeability barrier that can reduce penetration of antibiotics but cannot affect intracellular steady-state concentrations of drugs. The two-membrane envelopes are further reinforced by active efflux transporters that expel antibiotics from cells against their concentration gradients. The major mechanism of antibiotic resistance in Gram(-) pathogens is the active efflux of drugs, which acts synergistically with the low permeability barrier of the OM and other mutational and plasmid-borne mechanisms of antibiotic resistance.
- Authors:
-
[1];
[2];
[3];
[1]
- Univ. of Oklahoma, Norman, OK (United States)
- St. Louis Univ., MI (United States)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1772625
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Accounts of Chemical Research
- Additional Journal Information:
- Journal Volume: 54; Journal Issue: 4; Journal ID: ISSN 0001-4842
- Publisher:
- American Chemical Society
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Inhibitors; Antibiotic resistance; Antimicrobial agents; Bacteria; Membranes
Citation Formats
Zgurskaya, Helen I., Walker, John K., Parks, Jerry M., and Rybenkov, Valentin V. Multidrug Efflux Pumps and the Two-Faced Janus of Substrates and Inhibitors. United States: N. p., 2021.
Web. doi:10.1021/acs.accounts.0c00843.
Zgurskaya, Helen I., Walker, John K., Parks, Jerry M., & Rybenkov, Valentin V. Multidrug Efflux Pumps and the Two-Faced Janus of Substrates and Inhibitors. United States. https://doi.org/10.1021/acs.accounts.0c00843
Zgurskaya, Helen I., Walker, John K., Parks, Jerry M., and Rybenkov, Valentin V. Thu .
"Multidrug Efflux Pumps and the Two-Faced Janus of Substrates and Inhibitors". United States. https://doi.org/10.1021/acs.accounts.0c00843. https://www.osti.gov/servlets/purl/1772625.
@article{osti_1772625,
title = {Multidrug Efflux Pumps and the Two-Faced Janus of Substrates and Inhibitors},
author = {Zgurskaya, Helen I. and Walker, John K. and Parks, Jerry M. and Rybenkov, Valentin V.},
abstractNote = {Antibiotics are miracle drugs that can cure infectious bacterial diseases. However, their utility is challenged by antibiotic resistant bacteria emerging in clinics and straining the modern medicine and our ways of life. Certain bacteria such as Gram-negative (Gram(- )) and Mycobacteriales species are intrinsically resistant to most clinical antibiotics and can further gain multidrug resistance through mutations and plasmid acquisition. These species stand out by the presence of an additional external lipidic membranes (the outer membrane, OM) that are composed of unique glycolipids. Although formidable, the OM is a passive permeability barrier that can reduce penetration of antibiotics but cannot affect intracellular steady-state concentrations of drugs. The two-membrane envelopes are further reinforced by active efflux transporters that expel antibiotics from cells against their concentration gradients. The major mechanism of antibiotic resistance in Gram(-) pathogens is the active efflux of drugs, which acts synergistically with the low permeability barrier of the OM and other mutational and plasmid-borne mechanisms of antibiotic resistance.},
doi = {10.1021/acs.accounts.0c00843},
journal = {Accounts of Chemical Research},
number = 4,
volume = 54,
place = {United States},
year = {Thu Feb 04 00:00:00 EST 2021},
month = {Thu Feb 04 00:00:00 EST 2021}
}
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