Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa.

ACS Infectious Diseases
Connor J CooperHelen I Zgurskaya

Abstract

The permeability barrier of Gram-negative cell envelopes is the major obstacle in the discovery and development of new antibiotics. In Gram-negative bacteria, these difficulties are exacerbated by the synergistic interaction between two biochemically distinct phenomena, the low permeability of the outer membrane (OM) and active multidrug efflux. In this study, we used Pseudomonas aeruginosa and Escherichia coli strains with controllable permeability barriers, achieved through hyperporination of the OMs and varied efflux capacities, to evaluate the contributions of each of the barriers to protection from antibacterials. We analyzed antibacterial activities of β-lactams and fluoroquinolones, antibiotics that are optimized for targets in the periplasm and the cytoplasm, respectively, and performed a machine learning-based analysis to identify physicochemical descriptors that best classify their relative potencies. Our results show that the molecular properties selected by active efflux and the OM barriers are different for the two species. Antibiotic activity in P. aeruginosa was better classified by electrostatic and surface area properties, whereas topology, physical properties, and atom or bond counts best capture the behavior ...Continue Reading

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Citations

Apr 21, 2019·Medicinal Research Reviews·Andraž LamutTihomir Tomašič
Jun 6, 2019·Annals of the New York Academy of Sciences·Helen I Zgurskaya, Valentin V Rybenkov
Oct 5, 2019·Future Medicinal Chemistry·Beatriz Suay-GarcíaGerardo M Antón-Fos
Feb 6, 2020·International Journal of Molecular Sciences·Alessio AtzoriPaolo Ruggerone
Oct 31, 2020·Future Medicinal Chemistry·Kyle E MurphyAmanda L Wolfe
Feb 5, 2021·Accounts of Chemical Research·Helen I ZgurskayaValentin V Rybenkov
Nov 18, 2020·Nature Chemical Biology·Shibin ZhaoDerek S Tan
Mar 12, 2021·Advanced Drug Delivery Reviews·Henni-Karoliina RopponenClaus-Michael Lehr
Mar 17, 2021·Chemical Reviews·Jigneshkumar Dahyabhai PrajapatiMathias Winterhalter
Feb 8, 2020·Biochimica Et Biophysica Acta. General Subjects·Adam T GreenHelen I Zgurskaya
May 29, 2021·RSC Medicinal Chemistry·Henni-Karoliina RopponenAnna K H Hirsch
Jun 3, 2021·Antibiotics·Silvia Acosta-GutiérrezMatteo Ceccarelli
Jul 31, 2021·Proceedings of the National Academy of Sciences of the United States of America·Johanna UdeDirk Bumann
May 27, 2020·Journal of Chemical Information and Modeling·Rachael A MansbachS Gnanakaran
May 10, 2019·The Journal of Physical Chemistry. B·Alessio AtzoriPaolo Ruggerone
Jul 13, 2021·Antimicrobial Agents and Chemotherapy·Justyna W AdamiakHelen I Zgurskaya

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