Bedaquiline resistance: a predictable consequence of a game-changing drug?

Bedaquiline's (BDQ) incorporation into the recommended treatment for drug-resistant tuberculosis (DR-TB) has ushered in a new era of highly effective, shorter course, all-oral regimens. Unfortunately, as the uptake of BDQ-based regimens has increased, so has the emergence of BDQ resistance. In a recent ASM Case Reports article, M. Richard-Greenblatt, R. Bagga, C. Duncan, M. J. Billick, et al. (ASM Case Rep 2:e00126-25, 2025, https://doi.org/10.1128/asmcr.00126-25) reported on a patient with treatment-emergent extensively drug-resistant (XDR) TB, whose isolate harbored a novel loss-of-function pepQ mutation, with resulting BDQ resistance. This commentary briefly highlights the benefits of BDQ-based DR-TB therapy, while also reviewing data related to the growing challenge posed by BDQ resistance.