1. Microbiology and Infectious Disease
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Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation

  1. Swarnava Chaudhuri
  2. Liping Li
  3. Matthew Zimmerman
  4. Yuemeng Chen
  5. Yu-Xiang Chen
  6. Melody N Toosky
  7. Michelle Gardner
  8. Miaomiao Pan
  9. Yang-Yang Li
  10. Qingwen Kawaji
  11. Jun-Hao Zhu
  12. Hong-Wei Su
  13. Amanda J Martinot
  14. Eric J Rubin
  15. Veronique Anne Dartois  Is a corresponding author
  16. Babak Javid  Is a corresponding author
  1. Tsinghua University School of Medicine, China
  2. Rutgers, The State University of New Jersey, United States
  3. Harvard TH Chan School of Public Health, United States
  4. Harvard Medical School, United States
Research Article
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Cite this article as: eLife 2018;7:e36782 doi: 10.7554/eLife.36782

Abstract

Most bacteria use an indirect pathway to generate aminoacylated glutamine and/or asparagine tRNAs. Clinical isolates of Mycobacterium tuberculosis with increased rates of error in gene translation (mistranslation) involving the indirect tRNA-aminoacylation pathway have increased tolerance to the first-line antibiotic rifampicin. Here, we identify that the aminoglycoside kasugamycin can specifically decrease mistranslation due to the indirect tRNA pathway. Kasugamycin but not the aminoglycoside streptomycin, can limit emergence of rifampicin resistance in vitro and increases mycobacterial susceptibility to rifampicin both in vitro and in a murine model of infection. Moreover, despite parenteral administration of kasugamycin being unable to achieve the in vitro minimum inhibitory concentration, kasugamycin alone was able to significantly restrict growth of Mycobacterium tuberculosis in mice. These data suggest that pharmacologically reducing mistranslation may be a novel mechanism for targeting bacterial adaptation.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Swarnava Chaudhuri

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Liping Li

    Public Health Research Institute, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Matthew Zimmerman

    Public Health Research Institute, Rutgers, The State University of New Jersey, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yuemeng Chen

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  5. Yu-Xiang Chen

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  6. Melody N Toosky

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  7. Michelle Gardner

    Department of Immunology and Infectious Diseases, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Miaomiao Pan

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  9. Yang-Yang Li

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  10. Qingwen Kawaji

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  11. Jun-Hao Zhu

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  12. Hong-Wei Su

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  13. Amanda J Martinot

    Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Eric J Rubin

    Department of Immunology and Infectious Disease, Harvard TH Chan School of Public Health, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5120-962X
  15. Veronique Anne Dartois

    Public Health Research Insitute, Rutgers, The State University of New Jersey, Newark, United States
    For correspondence
    veronique.dartois@rutgers.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9470-5009
  16. Babak Javid

    Centre for Global Health and Infectious Diseases, Tsinghua University School of Medicine, Beijing, China
    For correspondence
    bjavid@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6354-6305

Funding

Bill and Melinda Gates Foundation (OPP1109789)

  • Babak Javid

Wellcome (207487/B/17/Z)

  • Babak Javid

National Natural Science Foundation of China (31570129)

  • Babak Javid

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

Ethics

Animal experimentation: All mouse infection and treatment experiments were approved by the Institutional Animal Care and Use committee of Rutgers University and mouse toxicity studies were approved by the Institutional Animal Care and Use Committee of Tsinghua University under protocol number 17-BJ2.

Reviewing Editor

  1. Madhukar Pai, McGill University, Canada

Publication history

  1. Received: March 19, 2018
  2. Accepted: August 27, 2018
  3. Accepted Manuscript published: August 28, 2018 (version 1)
  4. Version of Record published: September 27, 2018 (version 2)

Copyright

© 2018, Chaudhuri 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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