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Isocitrate lyase mediates broad antibiotic tolerance in Mycobacterium tuberculosis

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  • Madhumitha Nandakumar

    (Weill Cornell Medical College
    Weill Cornell Medical College)

  • Carl Nathan

    (Weill Cornell Medical College)

  • Kyu Y. Rhee

    (Weill Cornell Medical College
    Weill Cornell Medical College)

Abstract

Mycobacterium tuberculosis (Mtb) is a persistent intracellular pathogen intrinsically tolerant to most antibiotics. However, the specific factors that mediate this tolerance remain incompletely defined. Here we apply metabolomic profiling to discover a common set of metabolic changes associated with the activities of three clinically used tuberculosis drugs, isoniazid, rifampicin and streptomycin. Despite targeting diverse cellular processes, all three drugs trigger activation of Mtb’s isocitrate lyases (ICLs), metabolic enzymes commonly assumed to be involved in replenishing of tricarboxylic acid (TCA) cycle intermediates. We further show that ICL-deficient Mtb strains are significantly more susceptible than wild-type Mtb to all three antibiotics, and that this susceptibility can be chemically rescued when Mtb is co-incubated with an antioxidant. These results identify a previously undescribed role for Mtb’s ICLs in antioxidant defense as a mechanism of antibiotic tolerance.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms5306
    DOI: 10.1038/ncomms5306
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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. 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.

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