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Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline

Author

Listed:
  • Boatema Ofori-Anyinam

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

  • Meagan Hamblin

    (Broad Institute of MIT and Harvard
    Eversana Consulting)

  • Miranda L. Coldren

    (Seattle Children’s Research Institute)

  • Barry Li

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

  • Gautam Mereddy

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

  • Mustafa Shaikh

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

  • Avi Shah

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

  • Courtney Grady

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

  • Navpreet Ranu

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    insitro)

  • Sean Lu

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

  • Paul C. Blainey

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    Koch Institute of Integrative Cancer Research at MIT)

  • Shuyi Ma

    (Seattle Children’s Research Institute
    University of Washington
    University of Washington
    University of Washington)

  • James J. Collins

    (Broad Institute of MIT and Harvard
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Jason H. Yang

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

Abstract

Multidrug-resistant tuberculosis (MDR-TB), defined as resistance to the first-line drugs isoniazid and rifampin, is a growing source of global mortality and threatens global control of tuberculosis disease. The diarylquinoline bedaquiline has recently emerged as a highly efficacious drug against MDR-TB and kills Mycobacterium tuberculosis by inhibiting mycobacterial ATP synthase. However, the mechanisms underlying bedaquiline’s efficacy against MDR-TB remain unknown. Here we investigate bedaquiline hyper-susceptibility in drug-resistant Mycobacterium tuberculosis using systems biology approaches. We discovered that MDR clinical isolates are commonly sensitized to bedaquiline. This hypersensitization is caused by several physiological changes induced by deficient catalase activity. These include enhanced accumulation of reactive oxygen species, increased susceptibility to DNA damage, induction of sensitizing transcriptional programs, and metabolic repression of several biosynthetic pathways. In this work we demonstrate how resistance-associated changes in bacterial physiology can mechanistically induce collateral antimicrobial drug sensitivity and reveal druggable vulnerabilities in antimicrobial resistant pathogens.

Suggested Citation

  • Boatema Ofori-Anyinam & Meagan Hamblin & Miranda L. Coldren & Barry Li & Gautam Mereddy & Mustafa Shaikh & Avi Shah & Courtney Grady & Navpreet Ranu & Sean Lu & Paul C. Blainey & Shuyi Ma & James J. C, 2024. "Catalase activity deficiency sensitizes multidrug-resistant Mycobacterium tuberculosis to the ATP synthase inhibitor bedaquiline," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53933-8
    DOI: 10.1038/s41467-024-53933-8
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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.
    2. Eachan O. Johnson & Emily LaVerriere & Emma Office & Mary Stanley & Elisabeth Meyer & Tomohiko Kawate & James E. Gomez & Rebecca E. Audette & Nirmalya Bandyopadhyay & Natalia Betancourt & Kayla Delano, 2019. "Large-scale chemical–genetics yields new M. tuberculosis inhibitor classes," Nature, Nature, vol. 571(7763), pages 72-78, July.
    3. Anil Koul & Luc Vranckx & Neeraj Dhar & Hinrich W.H. Göhlmann & Emre Özdemir & Jean-Marc Neefs & Melanie Schulz & Ping Lu & Ejvind Mørtz & John D. McKinney & Koen Andries & Dirk Bald, 2014. "Delayed bactericidal response of Mycobacterium tuberculosis to bedaquiline involves remodelling of bacterial metabolism," Nature Communications, Nature, vol. 5(1), pages 1-10, May.
    4. Erol S. Kavvas & Laurence Yang & Jonathan M. Monk & David Heckmann & Bernhard O. Palsson, 2020. "A biochemically-interpretable machine learning classifier for microbial GWAS," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    5. James E. Galagan & Kyle Minch & Matthew Peterson & Anna Lyubetskaya & Elham Azizi & Linsday Sweet & Antonio Gomes & Tige Rustad & Gregory Dolganov & Irina Glotova & Thomas Abeel & Chris Mahwinney & Ad, 2013. "The Mycobacterium tuberculosis regulatory network and hypoxia," Nature, Nature, vol. 499(7457), pages 178-183, July.
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