Stefan Niemann, a CRyPTIC partner, led this combined experimental and modelling study looking at how resistance is conferred to bedaquline and clofazimine in Mycobacterial tuberculosis.
The CRyPTIC project provided 14,151 clinical isolates, each with minimum inhibitory concentrations (MICs) to bedaquiline and clofazimine. This dataset was used to pinpoint genetic variation in Rv0678, a transcription regulator of a key efflux pump, as the main source of elevated MICs. The authors carried out evolutionary experiments on Rv0678 and were able to relate them to four major resistance mechanisms: impairment of DNA binding, reduction in protein stability, disruption of protein dimerization and reduction in affinity for its fatty acid ligand.
A preprint is freely available to download.
- Sonnenkalb L, et al. (2021) Deciphering Bedaquiline and Clofazimine Resistance in Tuberculosis : An Evolutionary Medicine Approach. bioRxiv doi:101101/20210319436148.