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MSMEG_1963 and MSMEG_5597 Genes, but Not inhA, Modulate Mycobacterium smegmatis Resistance to Tryptanthrins

  • GENETICS OF MICROORGANISMS
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Abstract

The spread of drug-resistant strains of Mycobacterium tuberculosis is a major threat to the global control of tuberculosis (TB), urging the need to constantly develop new anti-TB drugs. Tryptanthrins are convenient compounds for the development of candidate anti-TB drugs due to the easy synthesis, low toxicity, and antimycobacterial activity on both drug-susceptible and drug-resistant M. tuberculosis strains. Enoyl-acyl carrier protein reductase InhA was previously predicted in silico as a possible target for tryptanthrins, while spontaneous tryptanthrin-resistant M. smegmatis mutants were found to have mutations in the MSMEG_1963, MSMEG_4427, and MSMEG_5597 genes. Using the approaches of reverse genetics, we demonstrate that mutations in the MSMEG_1963 and MSMEG_5597 genes lead to a loss of function of their encoded transcriptional repressors and lead to resistance to tryptanthrins. We show that mutations in MSMEG_1963 and MSMEG_5597 lead to overexpression of MSMEG_1964 and MSMEG_5596, respectively, which encode enzymes potentially involved in redox inactivation of tryptanthrins. We also show that InhA is not a biotarget of tryptanthrins, as its overexpression does not affect susceptibility of mycobacteria to tryptanthrins.

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ACKNOWLEDGEMENTS

We are grateful to D.B. Salunke (Department of Chemistry and Centre of Advanced Studies in Chemistry, Panjab University, India) and P. Kendrekar (Unit for Drug Discovery Research, Department of Health Sciences, Central University of Technology, South African Republic) for providing tryptanthrin compounds for the studies.

Funding

This work was supported by a grant from the President of the Russian Federation for young Russian scientists—candidates of sciences, MK-797.2020.4.

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Authors and Affiliations

  1. Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333, Moscow, Russia

    S. G. Frolova, V. N. Danilenko & D. A. Maslov

  2. Moscow Institute of Physics and Technology (State University), 141701, Dolgoprudny, Moscow oblast, Russia

    S. G. Frolova

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  1. S. G. Frolova
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  2. V. N. Danilenko
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  3. D. A. Maslov
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Correspondence to D. A. Maslov.

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The authors declare that they have no conflicts of interest. This article does not contain any studies involving animals or human participants performed by any of the authors.

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Translated by A. Lisenkova

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Frolova, S.G., Danilenko, V.N. & Maslov, D.A. MSMEG_1963 and MSMEG_5597 Genes, but Not inhA, Modulate Mycobacterium smegmatis Resistance to Tryptanthrins. Russ J Genet 58, 1051–1058 (2022). https://doi.org/10.1134/S1022795422090083

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