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CinA mediates multidrug tolerance in Mycobacterium tuberculosis

Author

Listed:
  • Kaj M. Kreutzfeldt

    (Weill Cornell Medical College)

  • Robert S. Jansen

    (Weill Cornell Medical College
    Radboud University)

  • Travis E. Hartman

    (Weill Cornell Medical College)

  • Alexandre Gouzy

    (Weill Cornell Medical College)

  • Ruojun Wang

    (Weill Cornell Medical College
    Princeton University)

  • Inna V. Krieger

    (Texas A&M University)

  • Matthew D. Zimmerman

    (Hackensack Meridian Health)

  • Martin Gengenbacher

    (Hackensack Meridian Health)

  • Jansy P. Sarathy

    (Hackensack Meridian Health)

  • Min Xie

    (Hackensack Meridian Health)

  • Véronique Dartois

    (Hackensack Meridian Health)

  • James C. Sacchettini

    (Texas A&M University)

  • Kyu Y. Rhee

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Dirk Schnappinger

    (Weill Cornell Medical College)

  • Sabine Ehrt

    (Weill Cornell Medical College)

Abstract

The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we define the Mtb protein CinA as a major determinant of drug tolerance and as a potential target to shorten TB chemotherapy. By reducing the fraction of drug-tolerant persisters, genetic inactivation of cinA accelerated killing of Mtb by four antibiotics in clinical use: isoniazid, ethionamide, delamanid and pretomanid. Mtb ΔcinA was killed rapidly in conditions known to impede the efficacy of isoniazid, such as during nutrient starvation, during persistence in a caseum mimetic, in activated macrophages and during chronic mouse infection. Deletion of CinA also increased in vivo killing of Mtb by BPaL, a combination of pretomanid, bedaquiline and linezolid that is used to treat highly drug-resistant TB. Genetic and drug metabolism studies suggest that CinA mediates drug tolerance via cleavage of NAD-drug adducts.

Suggested Citation

  • Kaj M. Kreutzfeldt & Robert S. Jansen & Travis E. Hartman & Alexandre Gouzy & Ruojun Wang & Inna V. Krieger & Matthew D. Zimmerman & Martin Gengenbacher & Jansy P. Sarathy & Min Xie & Véronique Dartoi, 2022. "CinA mediates multidrug tolerance in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29832-1
    DOI: 10.1038/s41467-022-29832-1
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    References listed on IDEAS

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    1. Michael A DeJesus & Chaitra Ambadipudi & Richard Baker & Christopher Sassetti & Thomas R Ioerger, 2015. "TRANSIT - A Software Tool for Himar1 TnSeq Analysis," PLOS Computational Biology, Public Library of Science, vol. 11(10), pages 1-17, October.
    2. E. Hesper Rego & Rebecca E. Audette & Eric J. Rubin, 2017. "Deletion of a mycobacterial divisome factor collapses single-cell phenotypic heterogeneity," Nature, Nature, vol. 546(7656), pages 153-157, June.
    3. Madhumitha Nandakumar & Carl Nathan & Kyu Y. Rhee, 2014. "Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis," Nature Communications, Nature, vol. 5(1), pages 1-10, September.
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    Cited by:

    1. Miljan Stupar & Lendl Tan & Edward D. Kerr & Christopher J. Voss & Brian M. Forde & Benjamin L. Schulz & Nicholas P. West, 2024. "TcrXY is an acid-sensing two-component transcriptional regulator of Mycobacterium tuberculosis required for persistent infection," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Katherine A. Abrahams & Sarah M. Batt & Sudagar S. Gurcha & Natacha Veerapen & Ghader Bashiri & Gurdyal S. Besra, 2023. "DprE2 is a molecular target of the anti-tubercular nitroimidazole compounds pretomanid and delamanid," Nature Communications, Nature, vol. 14(1), pages 1-10, December.

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