Response of to the Cytochrome Inhibitor Q203.

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 complex in the mycobacterial respiratory chain, is currently evaluated in phase-2 clinical trials. Q203 has bacteriostatic activity against which can be converted to bactericidal activity by concurrently inhibiting an alternative branch of the mycobacterial respiratory chain, cytochrome . In contrast, non-tuberculous mycobacteria, such as show only very little sensitivity to Q203. In this report, we investigated factors that employs to adapt to Q203 in the presence or absence of a functional cytochrome , especially regarding its terminal oxidases. In the presence of a functional cytochrome , responds to Q203 by increasing the expression of cytochrome as well as of cytochrome , whereas a -KO strain adapted to Q203 by increasing the expression of cytochrome . Interestingly, single-cell studies revealed cell-to-cell variability in drug adaptation. We also investigated the role of a putative second cytochrome isoform postulated for . Although this putative isoform showed differential expression in response to Q203 in the -KO strain, it did not display functional features similar to the characterised cytochrome variant.