P051

1:Research Center Borstel

Drug-resistant and multidrug-resistant tuberculosis (MDR-TB) remains a significant barrier to global tuberculosis (TB) control. Limited treatment access, diagnostic delays, and failures drive the emergence and spread of resistant Mycobacterium tuberculosis (MTBC) strains. The recent introduction of an all-oral, shortened MDR-TB regimen cantered around bedaquiline (BDQ) has marked a significant advancement for the treatment of MDR-TB patients. However, the rapid evolution of BDQ resistance compromises its long-term efficacy.

A comprehensive understanding of the molecular mechanisms underlying resistance is essential for improving diagnostics, optimizing treatment strategies, and guiding drug development. BDQ-resistant clinical MTBC strains commonly harbour mutations in the Rv0678 gene, although these typically confer only moderate resistance. To investigate the functional impact of different Rv0678 mutations, we analysed the transcriptomic profiles of three laboratory-generated BDQ-resistant MTBC clones (harbouring A99V, inversion or 274insA mutations in Rv0678) in the presence and absence of BDQ.

At baseline level, 242 differentially expressed genes (DEGs) were identified, with 7 DEGs shared across all three Rv0678 mutants. This highlights the transcriptomic diversity among clones carrying different mutations in the same resistance gene, emphasizing the variable impact of these mutations even in the absence of drug exposure. Upon BDQ treatment, we observed distinct transcriptional responses suggestive of broader metabolic reprogramming beyond the canonical Rv0678-mediated resistance mechanism. These findings reveal the dynamic and multifaceted nature of MTBC adaptation to drug pressure and underscore the importance of considering transcriptional responses when investigating resistance mechanisms. Ultimately, this work enhances our molecular understanding of the transcriptional landscape associated with BDQ resistance in MTBC.