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

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 in E. coli. In several cases, descriptor values that correspond to active antibiotics also correspond to significant barrier effects, highlighting the synergy between the two barriers where optimizing for onemore » barrier promotes strengthening of the other barrier. Furthermore, both barriers should be considered when optimizing antibiotics for favorable OM permeability, efflux evasion, or both.« less

Authors:
ORCiD logo [1];  [2];  [2]; ORCiD logo [3]; ORCiD logo [2]; ORCiD logo [4]; ORCiD logo [2]
  1. Univ. of Tennessee, Knoxville, TN (United States)
  2. Univ. of Oklahoma, Norman, OK (United States)
  3. Saint Louis Univ. School of Medicine, St. Louis, MO (United States)
  4. Univ. of Tennessee, Knoxville, TN (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:
1459303
Grant/Contract Number:  
AC05-00OR22725
Resource Type:
Accepted Manuscript
Journal Name:
ACS Infectious Diseases
Additional Journal Information:
Journal Volume: 4; Journal Issue: 8; Journal ID: ISSN 2373-8227
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; antibiotic permeation; Gram-negative bacteria; machine learning; multidrug efflux; outer membrane; physicochemical properties

Citation Formats

Cooper, Sarah J., Krishnamoorthy, Ganesh, Wolloscheck, David, Walker, John K., Rybenkov, Valentin V., Parks, Jerry M., and Zgurskaya, Helen I.. Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa. United States: N. p., 2018. Web. https://doi.org/10.1021/acsinfecdis.8b00036.
Cooper, Sarah J., Krishnamoorthy, Ganesh, Wolloscheck, David, Walker, John K., Rybenkov, Valentin V., Parks, Jerry M., & Zgurskaya, Helen I.. Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa. United States. https://doi.org/10.1021/acsinfecdis.8b00036
Cooper, Sarah J., Krishnamoorthy, Ganesh, Wolloscheck, David, Walker, John K., Rybenkov, Valentin V., Parks, Jerry M., and Zgurskaya, Helen I.. Mon . "Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa". United States. https://doi.org/10.1021/acsinfecdis.8b00036. https://www.osti.gov/servlets/purl/1459303.
@article{osti_1459303,
title = {Molecular Properties That Define the Activities of Antibiotics in Escherichia coli and Pseudomonas aeruginosa},
author = {Cooper, Sarah J. and Krishnamoorthy, Ganesh and Wolloscheck, David and Walker, John K. and Rybenkov, Valentin V. and Parks, Jerry M. and Zgurskaya, Helen I.},
abstractNote = {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 in E. coli. In several cases, descriptor values that correspond to active antibiotics also correspond to significant barrier effects, highlighting the synergy between the two barriers where optimizing for one barrier promotes strengthening of the other barrier. Furthermore, both barriers should be considered when optimizing antibiotics for favorable OM permeability, efflux evasion, or both.},
doi = {10.1021/acsinfecdis.8b00036},
journal = {ACS Infectious Diseases},
number = 8,
volume = 4,
place = {United States},
year = {2018},
month = {5}
}

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Figures / Tables:

Figure 1 Figure 1: Scaled MICs (green) and MIC ratios (blue) for antibiotics in P. aeruginosa sorted by antibiotic class and PAO1 MIC from lowest to highest within each class. Values were natural log-transformed and then scaled between 0 and 1. Gray squares indicate MIC ratios that are outside of the measurablemore » range. MICs report on relative potency and MIC ratios report on the dependence of antibiotic activity on efflux, the OM barrier, or both.« less

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    Works referencing / citing this record:

    Molecular Interactions of Carbapenem Antibiotics with the Multidrug Efflux Transporter AcrB of Escherichia coli
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