Acquisition of bedaquiline and clofazimine resistance in association with a novel loss-of-function mutation in the <i>pepQ</i> gene during treatment of multidrug-resistant tuberculosis

ABSTRACT Background Bedaquiline (BDQ) has transformed the management of multidrug-resistant (MDR) and rifampin-resistant tuberculosis (TB). Unfortunately, the expanded use of BDQ in these regimens has been accompanied by resistance, which is steadily increasing in certain regions of the world. Nonetheless, our understanding of the mechanisms behind BDQ resistance remains poor, limiting the utility of more rapid molecular or genomic-based diagnostics for the detection of BDQ-resistant isolates. Case Summary We describe an unusual case of a rapid, 2-year evolution of a fully susceptible Mycobacterium tuberculosis strain to extensively drug-resistant TB in a 44-year-old Canadian-born woman with Crohn’s disease. Comparative whole-genome sequencing captured the progressive development of resistance mutations and identified a novel loss-of-function mutation (Glu-177-STOP) in the M. tuberculosis pepQ gene that was associated with treatment failure while on BDQ and phenotypic BDQ/clofazimine (CFZ) cross-resistance. Therapeutic drug monitoring while on MDR therapy (daily ethambutol, pyrazinamide, linezolid, CFZ, and intravenous amikacin) detected low serum levels of CFZ, which was not addressed prior to the addition of BDQ to her 5-drug regimen and may have selected for BDQ/CFZ cross-resistance. Conclusion This case contributes to the limited clinical data implicating pepQ in BDQ/CFZ cross-resistance and describes a novel loss-of-function mutation associated with resistance. As our understanding of genotypic BDQ resistance remains elementary, when novel drug mutations arise, practitioners should consider their significance in the context of phenotypic drug susceptibility test results and the patient’s clinical response.