In Vitro Study of Stepwise Acquisition of rv0678 and atpE Mutations Conferring Bedaquiline Resistance

Bedaquiline resistance within may arise through efflux-based ( ) or target-based ( ) pathway mutations. mutant populations from each of five sequential steps in a passaging approach, using a pyrazinamide-resistant ATCC strain, were subjected to MIC determinations and whole-genome sequencing. Exposure to increasing bedaquiline concentrations resulted in increasing phenotypic resistance (up to >2 μg/ml) through MIC determination on solid medium (Middlebrook 7H10). mutations were dynamic, while mutations were fixed, once occurring. We present the following hypothesis for emergence of bedaquiline resistance: mutations may be the first transient step in low-level resistance acquisition, followed by high-level resistance due to fixed mutations.