Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

Chauhan, Priyanka; van der Meulen, Santhe Amber; Simões Caetano, João Miguel; Goojani, Hojjat Ghasemi; Botman, Dennis; van Spanning, Rob; Lill, Holger; Bald, Dirk

doi:10.3390/ijms231810331

Open AccessArticle

Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

by

Priyanka Chauhan

^*,

Santhe Amber van der Meulen

,

João Miguel Simões Caetano

,

Hojjat Ghasemi Goojani

,

Dennis Botman

,

Rob van Spanning

,

Holger Lill

and

Dirk Bald

^*

Amsterdam Institute for Life and Environment (A-LIFE), AIMMS, Faculty of Science, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, The Netherlands

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2022, 23(18), 10331; https://doi.org/10.3390/ijms231810331

Submission received: 16 August 2022 / Revised: 31 August 2022 / Accepted: 1 September 2022 / Published: 7 September 2022

(This article belongs to the Special Issue Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0)

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Abstract

For the design of next-generation tuberculosis chemotherapy, insight into bacterial defence against drugs is required. Currently, targeting respiration has attracted strong attention for combatting drug-resistant mycobacteria. Q203 (telacebec), an inhibitor of the cytochrome bcc complex in the mycobacterial respiratory chain, is currently evaluated in phase-2 clinical trials. Q203 has bacteriostatic activity against M. tuberculosis, which can be converted to bactericidal activity by concurrently inhibiting an alternative branch of the mycobacterial respiratory chain, cytochrome bd. In contrast, non-tuberculous mycobacteria, such as Mycobacterium smegmatis, show only very little sensitivity to Q203. In this report, we investigated factors that M. smegmatis employs to adapt to Q203 in the presence or absence of a functional cytochrome bd, especially regarding its terminal oxidases. In the presence of a functional cytochrome bd, M. smegmatis responds to Q203 by increasing the expression of cytochrome bcc as well as of cytochrome bd, whereas a M. smegmatisbd-KO strain adapted to Q203 by increasing the expression of cytochrome bcc. Interestingly, single-cell studies revealed cell-to-cell variability in drug adaptation. We also investigated the role of a putative second cytochrome bd isoform postulated for M. smegmatis. Although this putative isoform showed differential expression in response to Q203 in the M. smegmatisbd-KO strain, it did not display functional features similar to the characterised cytochrome bd variant.

Keywords: Mycobacterium smegmatis; terminal oxidases; Q203; electron transport chain

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MDPI and ACS Style

Chauhan, P.; van der Meulen, S.A.; Simões Caetano, J.M.; Goojani, H.G.; Botman, D.; van Spanning, R.; Lill, H.; Bald, D. Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203. Int. J. Mol. Sci. 2022, 23, 10331. https://doi.org/10.3390/ijms231810331

AMA Style

Chauhan P, van der Meulen SA, Simões Caetano JM, Goojani HG, Botman D, van Spanning R, Lill H, Bald D. Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203. International Journal of Molecular Sciences. 2022; 23(18):10331. https://doi.org/10.3390/ijms231810331

Chicago/Turabian Style

Chauhan, Priyanka, Santhe Amber van der Meulen, João Miguel Simões Caetano, Hojjat Ghasemi Goojani, Dennis Botman, Rob van Spanning, Holger Lill, and Dirk Bald. 2022. "Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203" International Journal of Molecular Sciences 23, no. 18: 10331. https://doi.org/10.3390/ijms231810331

APA Style

Chauhan, P., van der Meulen, S. A., Simões Caetano, J. M., Goojani, H. G., Botman, D., van Spanning, R., Lill, H., & Bald, D. (2022). Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203. International Journal of Molecular Sciences, 23(18), 10331. https://doi.org/10.3390/ijms231810331

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Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

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