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Beta-lactamase dependent and independent evolutionary paths to high-level ampicillin resistance

Author

Listed:
  • Rotem Gross

    (Technion–Israel Institute of Technology)

  • Idan Yelin

    (Technion–Israel Institute of Technology)

  • Viktória Lázár

    (Technion–Israel Institute of Technology
    HCEMM-BRC Pharmacodynamic Drug Interaction Research Group
    HUN-REN Biological Research Centre)

  • Manoshi Sen Datta

    (Technion–Israel Institute of Technology
    University of California, Berkeley)

  • Roy Kishony

    (Technion–Israel Institute of Technology
    Technion–Israel Institute of Technology
    Technion–Israel Institute of Technology)

Abstract

The incidence of beta-lactam resistance among clinical isolates is a major health concern. A key method to study the emergence of antibiotic resistance is adaptive laboratory evolution. However, in the case of the beta-lactam ampicillin, bacteria evolved in laboratory settings do not recapitulate clinical-like resistance levels, hindering efforts to identify major evolutionary paths and their dependency on genetic background. Here, we used the Microbial Evolution and Growth Arena (MEGA) plate to select ampicillin-resistant Escherichia coli mutants with varying degrees of resistance. Whole-genome sequencing of resistant isolates revealed that ampicillin resistance was acquired via a combination of single-point mutations and amplification of the gene encoding beta-lactamase AmpC. However, blocking AmpC-mediated resistance revealed latent adaptive pathways: strains deleted for ampC were able to adapt through combinations of changes in genes involved in multidrug resistance encoding efflux pumps, transcriptional regulators, and porins. Our results reveal that combinations of distinct genetic mutations, accessible at large population sizes, can drive high-level resistance to ampicillin even independently of beta-lactamases.

Suggested Citation

  • Rotem Gross & Idan Yelin & Viktória Lázár & Manoshi Sen Datta & Roy Kishony, 2024. "Beta-lactamase dependent and independent evolutionary paths to high-level ampicillin resistance," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49621-2
    DOI: 10.1038/s41467-024-49621-2
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    1. Tomoya Maeda & Junichiro Iwasawa & Hazuki Kotani & Natsue Sakata & Masako Kawada & Takaaki Horinouchi & Aki Sakai & Kumi Tanabe & Chikara Furusawa, 2020. "High-throughput laboratory evolution reveals evolutionary constraints in Escherichia coli," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
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