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