Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhibitors
Abstract
Optimization of compound permeation into Gram-negative bacteria is one of the most challenging tasks in the development of antibacterial agents. Two permeability barriers–the passive diffusion barrier of the outer membrane (OM) and active drug efflux–act synergistically to protect cells from the antibacterial action of compounds. In Escherichia coli (E. coli) and relatives, these two barriers sieve compounds based on different physicochemical properties that are defined by their interactions with OM porins and efflux pumps, respectively. In this study, we critically tested the hypothesis that the best substrates and inhibitors of efflux pumps are compounds that can effectively permeate the OM and are available at relatively high concentrations in the periplasm. For this purpose, we filtered a large subset of the ZINC15 database of commercially available compounds for compounds containing a primary amine, a chemical feature known to facilitate the uptake through E. coli general porins. The assembled library was screened by ensemble docking to AcrA, the periplasmic component of the AcrAB-TolC efflux pump, followed by experimental testing of the top predicted binders for antibacterial activities, efflux recognition, and inhibition. In this work, we found that the filtered primary amine library is a rich source of compounds with efflux-inhibiting activities andmore »
- Authors:
-
[2];
[3];
[2];
[1]
- Univ. of Oklahoma, Norman, OK (United States)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Saint Louis University School of Medicine, MO (United States)
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE
- OSTI Identifier:
- 1894196
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Accepted Manuscript
- Journal Name:
- ACS Infectious Diseases
- Additional Journal Information:
- Journal Volume: 8; Journal Issue: 10; Journal ID: ISSN 2373-8227
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; multidrug efflux; efflux pump inhibitors; Gram-negative bacteria; outer membrane permeability
Citation Formats
Moniruzzaman, Mohammad, Cooper, Connor J., Uddin, Muhammad R., Walker, John K., Parks, Jerry M., and Zgurskaya, Helen I. Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhibitors. United States: N. p., 2022.
Web. doi:10.1021/acsinfecdis.2c00263.
Moniruzzaman, Mohammad, Cooper, Connor J., Uddin, Muhammad R., Walker, John K., Parks, Jerry M., & Zgurskaya, Helen I. Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhibitors. United States. https://doi.org/10.1021/acsinfecdis.2c00263
Moniruzzaman, Mohammad, Cooper, Connor J., Uddin, Muhammad R., Walker, John K., Parks, Jerry M., and Zgurskaya, Helen I. Wed .
"Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhibitors". United States. https://doi.org/10.1021/acsinfecdis.2c00263. https://www.osti.gov/servlets/purl/1894196.
@article{osti_1894196,
title = {Analysis of Orthogonal Efflux and Permeation Properties of Compounds Leads to the Discovery of New Efflux Pump Inhibitors},
author = {Moniruzzaman, Mohammad and Cooper, Connor J. and Uddin, Muhammad R. and Walker, John K. and Parks, Jerry M. and Zgurskaya, Helen I.},
abstractNote = {Optimization of compound permeation into Gram-negative bacteria is one of the most challenging tasks in the development of antibacterial agents. Two permeability barriers–the passive diffusion barrier of the outer membrane (OM) and active drug efflux–act synergistically to protect cells from the antibacterial action of compounds. In Escherichia coli (E. coli) and relatives, these two barriers sieve compounds based on different physicochemical properties that are defined by their interactions with OM porins and efflux pumps, respectively. In this study, we critically tested the hypothesis that the best substrates and inhibitors of efflux pumps are compounds that can effectively permeate the OM and are available at relatively high concentrations in the periplasm. For this purpose, we filtered a large subset of the ZINC15 database of commercially available compounds for compounds containing a primary amine, a chemical feature known to facilitate the uptake through E. coli general porins. The assembled library was screened by ensemble docking to AcrA, the periplasmic component of the AcrAB-TolC efflux pump, followed by experimental testing of the top predicted binders for antibacterial activities, efflux recognition, and inhibition. In this work, we found that the filtered primary amine library is a rich source of compounds with efflux-inhibiting activities and identified efflux pump inhibitors with novel chemical scaffolds effective against E. coli AcrAB-TolC and efflux pumps of multidrug-resistant clinical isolates of Acinetobacter baumannii. However, primary amines are not required for the recognition of compounds by efflux pumps and their efflux-inhibitory activities.},
doi = {10.1021/acsinfecdis.2c00263},
journal = {ACS Infectious Diseases},
number = 10,
volume = 8,
place = {United States},
year = {Wed Sep 07 00:00:00 EDT 2022},
month = {Wed Sep 07 00:00:00 EDT 2022}
}
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