IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-29832-1.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-29832-1
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-29832-1?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. 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.
    2. 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.
    3. 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.
    Full references (including those not matched with items on IDEAS)

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    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.

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Simon R. Green & Susan H. Davis & Sebastian Damerow & Curtis A. Engelhart & Michael Mathieson & Beatriz Baragaña & David A. Robinson & Jevgenia Tamjar & Alice Dawson & Fabio K. Tamaki & Kirsteen I. Bu, 2022. "Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    2. Amir Arastehfar & Farnaz Daneshnia & Nathaly Cabrera & Suyapa Penalva-Lopez & Jansy Sarathy & Matthew Zimmerman & Erika Shor & David S. Perlin, 2023. "Macrophage internalization creates a multidrug-tolerant fungal persister reservoir and facilitates the emergence of drug resistance," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Dmitry Leshchiner & Federico Rosconi & Bharathi Sundaresh & Emily Rudmann & Luisa Maria Nieto Ramirez & Andrew T. Nishimoto & Stephen J. Wood & Bimal Jana & Noemí Buján & Kaicheng Li & Jianmin Gao & M, 2022. "A genome-wide atlas of antibiotic susceptibility targets and pathways to tolerance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    4. Samuel Miravet-Verde & Rocco Mazzolini & Carolina Segura-Morales & Alicia Broto & Maria Lluch-Senar & Luis Serrano, 2024. "ProTInSeq: transposon insertion tracking by ultra-deep DNA sequencing to identify translated large and small ORFs," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    5. Maxime Mistretta & Mena Cimino & Pascal Campagne & Stevenn Volant & Etienne Kornobis & Olivier Hebert & Christophe Rochais & Patrick Dallemagne & Cédric Lecoutey & Camille Tisnerat & Alban Lepailleur , 2024. "Dynamic microfluidic single-cell screening identifies pheno-tuning compounds to potentiate tuberculosis therapy," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    6. Ian L. Sparks & Takehiro Kado & Malavika Prithviraj & Japinder Nijjer & Jing Yan & Yasu S. Morita, 2024. "Lipoarabinomannan mediates localized cell wall integrity during division in mycobacteria," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Henri Voedts & Sean P. Kennedy & Guennadi Sezonov & Michel Arthur & Jean-Emmanuel Hugonnet, 2022. "Genome-wide identification of genes required for alternative peptidoglycan cross-linking in Escherichia coli revealed unexpected impacts of β-lactams," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    8. Di Qu & Peng Ge & Laure Botella & Sae Woong Park & Ha-Na Lee & Natalie Thornton & James M. Bean & Inna V. Krieger & James C. Sacchettini & Sabine Ehrt & Courtney C. Aldrich & Dirk Schnappinger, 2024. "Mycobacterial biotin synthases require an auxiliary protein to convert dethiobiotin into biotin," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29832-1. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.