Response of Mycobacterium smegmatis to the Cytochrome bcc Inhibitor Q203

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

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

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. smegmatis bd-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. smegmatis bd-KO strain, it did not display functional features similar to the characterised cytochrome bd variant.

Original languageEnglish
Article number10331
Pages (from-to)1-17
Number of pages17
JournalInternational Journal of Molecular Sciences
Volume23
Issue number18
DOIs
Publication statusPublished - 2 Sept 2022

Bibliographical note

Special Issue: Antimicrobial Resistance, Molecular Mechanisms and Fight Strategies 2.0.

Funding Information:
This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 713669.

Publisher Copyright:
© 2022 by the authors.

Funding

This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 713669.

Keywords

  • electron transport chain
  • Mycobacterium smegmatis
  • Q203
  • terminal oxidases

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