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Antimicrob Agents Chemother. 2019 Nov 25. pii: AAC.01899-19. doi: 10.1128/AAC.01899-19. [Epub ahead of print]

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

Author information

1
Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel.
2
McGill University Health Center, Montreal, Quebec, Canada.
3
The Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Haifa.
4
Cornell Veterinary College, Cornell University, Ithaca, NY, USA.
5
Koret School of Veterinary Medicine, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, Israel daniel.barkan@mail.huji.ac.il.

Abstract

Background: Isoniazid (INH) is a cornerstone of antitubercular therapy. M. tuberculosis-complex bacteria are the only mycobacteria sensitive to clinically-relevant concentrations of INH. All other mycobacteria, including M. marinum and M. avium paratuberculosis (MAP) are resistant. INH needs to be activated by bacterial KatG to inhibit mycobacterial growth, we tested the role of the differences between Mtb KatG and that of other mycobacteria in INH sensitivity.Methods: We cloned the M. bovis katG into M. marinum and MAP, and measured the minimal inhibitory concentration (MIC) of INH. We recombinantly expressed KatG of these mycobacteria, and tested their in-vitro binding to, and activation of, INH.Results: Introduction of katG from M. bovis into M. marinum and MAP rendered them 20-30 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 NTM's KatG proteins showed lower affinity to INH and substantially lower enzymatic capacity for the conversion of INH into the active form in NTM.Conclusions: The KatG of M. marinum and MAP are substantially less effective in INH activation than that of Mtb, explaining their relative INH insensitivity. These data indicate that the Mtb-complex KatG is divergent from the KatG of NTM, such that there is a reciprocal relationship between resisting host defenses and INH resistance. Studying bacteria where KatG is functionally active but does not activate INH, may aid in understanding Mtb INH-resistance mechanisms, and suggest paths to overcome them.

PMID:
31767723
DOI:
10.1128/AAC.01899-19

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