Efficacy of β-lactam\β-lactamase inhibitor combination is linked to WhiB4 mediated changes in redox physiology of Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis (Mtb) expresses a broad-spectrum β-lactamase (BlaC) that mediates resistance to one of the highly effective antibacterials, β-lactams. Nonetheless, β-lactams showed mycobactericidal activity in combination with β-lactamase inhibitor, clavulanate (Clav). However, the mechanistic aspects of how Mtb responds to β-lactams such as Amoxicillin in combination with Clav (referred as Augmentin [AG]) are not clear. Here, we identified cytoplasmic redox potential and intracellular redox sensor, WhiB4, as key determinants of mycobacterial resistance against AG. Using computer-based, biochemical, redox-biosensor, and genetic strategies, we uncovered a functional linkage between specific determinants of β-lactam resistance (e.g., β-lactamase) and redox potential in Mtb. We also describe the role of WhiB4 in coordinating the activity of β-lactamase in a redox-dependent manner to tolerate AG. Disruption of WhiB4 enhances AG tolerance, whereas overexpression potentiates AG activity against drug-resistant Mtb. Our findings suggest that AG can be exploited to diminish drug-resistance in Mtb through redox-based interventions. through redox-based interventions.

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Author details

  1. Saurabh MISHRA

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  2. Prashant Shukla

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  3. Ashima Bhaskar

    National Institute of Immunology, New Delhi, India
    Competing interests
    The authors declare that no competing interests exist.
  4. Kushi Anand

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  5. Priyanka Baloni

    Department of Biochemistry, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  6. Rajiv Kumar Jha

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  7. Abhilash Mohan

    Department of Biochemistry, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  8. Raju S Rajmani

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  9. Valakunja Nagaraja

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  10. Nagasuma Chandra

    Department of Biochemistry, Indian Institute of Science, Bangalore, India
    Competing interests
    The authors declare that no competing interests exist.
  11. Amit Singh

    Microbiology and Cell Biology, Indian Institute of Science, Bangalore, India
    For correspondence
    asingh@mcbl.iisc.ernet.in
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6761-1664

Funding

Department of Biotechnology , Ministry of Science and Technology (BT/PR5020/MED/29/1454/2012)

  • Amit Singh

Wellcome (WT-DBT/500034-Z-09-Z)

  • Amit Singh

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was carried out in strict accordance with the guidelines provided by the Committee for the Purpose of Control and Supervision on Experiments on Animals (CPCSEA), Government of India. The protocol was approved by the Committee on the Ethics of Animal Experiments of the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, India (Approval number: ICGEB/AH/2011/2/IMM-26). All efforts were made to minimize the suffering.

Reviewing Editor

  1. Bavesh D Kana, University of the Witwatersrand, South Africa

Publication history

  1. Received: January 31, 2017
  2. Accepted: May 24, 2017
  3. Accepted Manuscript published: May 26, 2017 (version 1)
  4. Version of Record published: June 16, 2017 (version 2)

Copyright

© 2017, MISHRA et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Saurabh MISHRA
  2. Prashant Shukla
  3. Ashima Bhaskar
  4. Kushi Anand
  5. Priyanka Baloni
  6. Rajiv Kumar Jha
  7. Abhilash Mohan
  8. Raju S Rajmani
  9. Valakunja Nagaraja
  10. Nagasuma Chandra
  11. Amit Singh
(2017)
Efficacy of β-lactam\β-lactamase inhibitor combination is linked to WhiB4 mediated changes in redox physiology of Mycobacterium tuberculosis
eLife 6:e25624.
https://doi.org/10.7554/eLife.25624

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