Differential sensitivity of mycobacteria to isoniazid is related to differences in katg-mediated enzymatic activation of the drug

Tali H. Reingewertz, Tom Meyer, Fiona McIntosh, Jaryd Sullivan, Michal Meir, Yung Fu Chang, Marcel A. Behr, Daniel Barkana*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Isoniazid (INH) is a cornerstone of antitubercular therapy. Mycobacterium tuberculosis complex bacteria are the only mycobacteria sensitive to clinically relevant concentrations of INH. All other mycobacteria, including M. marinum and M. avium subsp. paratuberculosis are resistant. INH requires activation by bacterial KatG to inhibit mycobacterial growth. We tested the role of the differences between M. tuberculosis KatG and that of other mycobacteria in INH sensitivity. We cloned the M. bovis katG gene into M. marinum and M. avium subsp. paratuberculosis and measured the MIC of INH. We recombinantly expressed KatG of these mycobacteria and tested in vitro binding to, and activation of, INH. Introduction of katG from M. bovis into M. marinum and M. avium subsp. paratuberculosis rendered them 20 to 30 times more sensitive to INH. Analysis of different katG sequences across the genus found KatG evolution diverged from RNA polymerase-defined mycobacterial evolution. Biophysical and biochemical tests of M. bovis and nontuberculous mycobacteria (NTM) KatG proteins showed lower affinity to INH and substantially lower enzymatic capacity for the conversion of INH into the active form in NTM. The KatG proteins of M. marinum and M. avium subsp. paratuberculosis are substantially less effective in INH activation than that of M. tuberculosis, explaining the relative INH insensitivity of these microbes. These data indicate that the M. tuberculosis complex KatG is divergent from the KatG of NTM, with a reciprocal relationship between resistance to host defenses and INH resistance. Studies of bacteria where KatG is functionally active but does not activate INH may aid in understanding M. tuberculosis INHresistance mechanisms, and suggest paths to overcome them.

Original languageAmerican English
Article numbere01899
JournalAntimicrobial Agents and Chemotherapy
Volume64
Issue number2
DOIs
StatePublished - 27 Jan 2020

Bibliographical note

Publisher Copyright:
© 2020 American Society for Microbiology. All rights reserved.

Keywords

  • Avium
  • Isoniazid
  • KatG
  • Marinum
  • Mycobacteria

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