Development of antibacterial compounds that constrain evolutionary pathways to resistance

  1. Yanmin Zhang
  2. Sourav Chowdhury
  3. João V Rodrigues
  4. Eugene I Shakhnovich  Is a corresponding author
  1. China Pharmaceutical University, China
  2. Harvard University, United States

Abstract

Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC50 50-75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3 resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC50) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which constrain evolutionary escape routes in pathogens.

Data availability

All the data is made available in the paper.

Article and author information

Author details

  1. Yanmin Zhang

    School of Science, China Pharmaceutical University, China Pharmaceutical University, Jiangsu 211198, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Sourav Chowdhury

    Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. João V Rodrigues

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5605-656X
  4. Eugene I Shakhnovich

    Department of Chemistry and Chemical Biology, Harvard University, Cambridge, United States
    For correspondence
    shakhnovich@chemistry.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4769-2265

Funding

National Institute of General Medical Sciences (NIH RO1 068670)

  • Sourav Chowdhury
  • João V Rodrigues
  • Eugene I Shakhnovich

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Christian R Landry, Université Laval, Canada

Publication history

  1. Received: November 1, 2020
  2. Accepted: July 13, 2021
  3. Accepted Manuscript published: July 19, 2021 (version 1)
  4. Version of Record published: August 3, 2021 (version 2)

Copyright

© 2021, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yanmin Zhang
  2. Sourav Chowdhury
  3. João V Rodrigues
  4. Eugene I Shakhnovich
(2021)
Development of antibacterial compounds that constrain evolutionary pathways to resistance
eLife 10:e64518.
https://doi.org/10.7554/eLife.64518
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