P024

The persistent challenge of drug resistant, and multi-drug-resistant tuberculosis (MDR-TB) continues to undermine current treatment strategies, with nearly half a million cases annually. Several factors including the long-term, complicated and often toxic treatment regimens, delayed diagnostics, and pharmacokinetic interactions facilitate the selection of drug resistant Mycobacterium tuberculosis (MTBC) complex strains, which then can be transmitted further.  Despite the success of a novel shortened all-oral MDR-TB treatment regiment, the observation of rapid bedaquiline (BDQ) resistance evolution, a pivotal component of this regiment, is of concern. Accordingly, a precise understanding of resistance mechanisms is key for effective diagnostics and treatment.

Nearly all BDQ resistances observed in clinical MTBC strains are linked to variants in Rv0678, despite having a moderate resistance profile. To elucidate the effect of different Rv0678 variants on MTBC strains, the transcriptomic landscape in presence and absence of the target drug BDQ was investigated on lab generated mutants. Initial investigations on the described mechanism of efflux pump mmpS5-mmpL5 revealed moderate expression of these pumps in the Rv0678 mutants, and enhanced expression under BDQ exposure. Notably, the susceptible wild type ancestor clone also exhibited increased expression of the efflux pumps when compared to untreated conditions. Temporal transcriptional changes indicated metabolic remodelling beyond the described resistance mechanism.

This study challenges our current understanding of Rv0678 functionality, and advances our understanding of resistance mechanisms of MTBC bacteria. These insights show potential for the development of more effective treatment strategies rooted in evolutionary medicine principles.