Identification of compensatory mutations in XDR-Mtb strains: understanding the dynamics and mechanisms of transmission.

Tuberculosis (TB) continues to be a major global public health threat. The development of drug resistance, and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis (Mtb) especially, pose a major problem to TB control. Transmission of XDR-Mtb strains is in conflict with the dogma that XDR-Mtb strains are less transmissible due to a cumulative fitness costs of resistance conferring mutations. For rifampicin resistant strains for example, it has been shown that mycobacteria can acquire compensatory mutations in the rpoC gene to overcome the fitness cost of resistance conferring mutations. Due to the limited access to large sample sets of XDR-Mtb strains, the transmissibility of XDR-Mtb strains and the effect of compensatory mutations to reverse the fitness cost remain poorly studied. The FWO-funded TORCH consortium houses a whole genome sequence database of around 1000 XDR-Mtb strains collected in the Western Cape Province in South Africa over a 14-year period (2006 to 2019). This exceptional dataset of XDR strains allows an in-depth analysis of XDR-TB transmission dynamics and its evolutionary mechanisms. By combining bioinformatics analyses (identifying XDR-Mtb associated genomic convergence) with spatio-temporal analyses of the XDR-Mtb strains by transmission status we expect to identify novel compensatory mutations and their relative importance to the transmission of XDR-Mtb strains.

Keywords:INFECTIONS

Disciplines:Analysis of next-generation sequence data, Bioinformatics of disease, Computational evolutionary biology, comparative genomics and population genomics, Molecular evolution, Phylogeny and comparative analysis

Project type:Collaboration project