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Collateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance

Author

Listed:
  • Dennis Y. Liu

    (Simon Fraser University)

  • Laura Phillips

    (Carleton University)

  • Darryl M. Wilson

    (Simon Fraser University)

  • Kelly M. Fulton

    (National Research Council Canada)

  • Susan M. Twine

    (Carleton University
    National Research Council Canada)

  • Alex Wong

    (Carleton University
    Texas A&M AgriLife)

  • Roger G. Linington

    (Simon Fraser University)

Abstract

The rapid emergence of antimicrobial resistance presents serious health challenges to the management of infectious diseases, a problem that is further exacerbated by slowing rates of antimicrobial drug discovery in recent years. The phenomenon of collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities to address both these challenges. Here, we present a high-throughput screening platform termed Collateral Sensitivity Profiling (CSP) to map the difference in bioactivity of large chemical libraries across 29 drug-resistant strains of E. coli. CSP screening of 80 commercial antimicrobials demonstrated multiple CS interactions. Further screening of a 6195-member natural product library revealed extensive CS relationships in nature. In particular, we report the isolation of known and new analogues of borrelidin A with potent CS activities against cephalosporin-resistant strains. Co-dosing ceftazidime with borrelidin A slows broader cephalosporin resistance with no recognizable resistance to borrelidin A itself.

Suggested Citation

  • Dennis Y. Liu & Laura Phillips & Darryl M. Wilson & Kelly M. Fulton & Susan M. Twine & Alex Wong & Roger G. Linington, 2023. "Collateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-37624-4
    DOI: 10.1038/s41467-023-37624-4
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    References listed on IDEAS

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    1. Qian Li & Shang Chen & Kui Zhu & Xiaoluo Huang & Yucheng Huang & Zhangqi Shen & Shuangyang Ding & Danxia Gu & Qiwen Yang & Hongli Sun & Fupin Hu & Hui Wang & Jiachang Cai & Bing Ma & Rong Zhang & Jian, 2022. "Collateral sensitivity to pleuromutilins in vancomycin-resistant Enterococcus faecium," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    2. Michelle F. Richter & Bryon S. Drown & Andrew P. Riley & Alfredo Garcia & Tomohiro Shirai & Riley L. Svec & Paul J. Hergenrother, 2017. "Predictive compound accumulation rules yield a broad-spectrum antibiotic," Nature, Nature, vol. 545(7654), pages 299-304, May.
    3. Daniel Nichol & Joseph Rutter & Christopher Bryant & Andrea M. Hujer & Sai Lek & Mark D. Adams & Peter Jeavons & Alexander R. A. Anderson & Robert A. Bonomo & Jacob G. Scott, 2019. "Antibiotic collateral sensitivity is contingent on the repeatability of evolution," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
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