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Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis

Author

Listed:
  • XinYue Wang

    (University of Otago)

  • William J. Jowsey

    (University of Otago)

  • Chen-Yi Cheung

    (University of Otago)

  • Caitlan J. Smart

    (University of Otago)

  • Hannah R. Klaus

    (University of Otago
    University of Auckland)

  • Noon EJ Seeto

    (University of Otago)

  • Natalie JE Waller

    (University of Otago)

  • Michael T. Chrisp

    (University of Otago)

  • Amanda L. Peterson

    (The University of Melbourne)

  • Boatema Ofori-Anyinam

    (Rutgers New Jersey Medical School
    Rutgers New Jersey Medical School)

  • Emily Strong

    (The University of Queensland)

  • Brunda Nijagal

    (The University of Melbourne)

  • Nicholas P. West

    (The University of Queensland)

  • Jason H. Yang

    (Rutgers New Jersey Medical School
    Rutgers New Jersey Medical School)

  • Peter C. Fineran

    (University of Otago
    University of Auckland
    University of Otago
    University of Otago)

  • Gregory M. Cook

    (University of Otago
    University of Auckland
    Translational Research Institute)

  • Simon A. Jackson

    (University of Otago
    University of Auckland)

  • Matthew B. McNeil

    (University of Otago
    University of Auckland)

Abstract

Drug-resistant strains of Mycobacterium tuberculosis are a major global health problem. Resistance to the front-line antibiotic isoniazid is often associated with mutations in the katG-encoded bifunctional catalase-peroxidase. We hypothesise that perturbed KatG activity would generate collateral vulnerabilities in isoniazid-resistant katG mutants, providing potential pathway targets to combat isoniazid resistance. Whole genome CRISPRi screens, transcriptomics, and metabolomics were used to generate a genome-wide map of cellular vulnerabilities in an isoniazid-resistant katG mutant strain of M. tuberculosis. Here, we show that metabolic and transcriptional remodelling compensates for the loss of KatG but in doing so generates vulnerabilities in respiration, ribosome biogenesis, and nucleotide and amino acid metabolism. Importantly, these vulnerabilities are more sensitive to inhibition in an isoniazid-resistant katG mutant and translated to clinical isolates. This work highlights how changes in the physiology of drug-resistant strains generates druggable vulnerabilities that can be exploited to improve clinical outcomes.

Suggested Citation

  • XinYue Wang & William J. Jowsey & Chen-Yi Cheung & Caitlan J. Smart & Hannah R. Klaus & Noon EJ Seeto & Natalie JE Waller & Michael T. Chrisp & Amanda L. Peterson & Boatema Ofori-Anyinam & Emily Stron, 2024. "Whole genome CRISPRi screening identifies druggable vulnerabilities in an isoniazid resistant strain of Mycobacterium tuberculosis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-54072-w
    DOI: 10.1038/s41467-024-54072-w
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    References listed on IDEAS

    as
    1. Natalie J. E. Waller & Chen-Yi Cheung & Gregory M. Cook & Matthew B. McNeil, 2023. "The evolution of antibiotic resistance is associated with collateral drug phenotypes in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
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