In this preprint we examine 14,151 clinical isolates drawn from the CRyPTIC dataset. Each isolate had its minimum inhibitory concentration (MIC) to bedaquiline and clofazimine measured and hence we were able to identify the transcription regulator Rv0678, as the current main source of elevated MICs to both these drugs.

Lindsay Sonnenkalb, who is studying for her PhD with Stefan Niemann, then evolved Mycobacterium tuberculosis strains under sub-lethal concentrations of both compounds and was able to identify 189 different Rv0678 genetic variants that confer elevated MICs to bedaquiline and clofazimine.

Detailed modelling of the protein structure allowed us to posit four main resistance mechanisms: impairment of DNA binding, reduction in protein stability, disruption of protein dimerization, and reduction in affinity for its fatty acid ligand.