Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation
- Tsinghua University School of Medicine, China
- Rutgers, The State University of New Jersey, United States
- Harvard TH Chan School of Public Health, United States
- Harvard Medical School, United States
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
Veronique Anne Dartois
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.
Reviewing Editor
- Madhukar Pai, McGill University, Canada
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.
Version history
- Received: March 19, 2018
- Accepted: August 27, 2018
- Accepted Manuscript published: August 28, 2018 (version 1)
- 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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Kasugamycin potentiates rifampicin and limits emergence of resistance in Mycobacterium tuberculosis by specifically decreasing mycobacterial mistranslation
eLife 7:e36782.
https://doi.org/10.7554/eLife.36782
