Patterns of compensatory mutations in rpoA/B/C genes of multidrug resistant M. tuberculosis in Uganda

Mutations in rpoB, a gene that encodes the bacterial RNA polymerase (RNAP) beta-subunit, can cause high level resistance to rifampicin. Most rifampicin-resistant Mycobacterium tuberculosis clinical isolates possess mutations in an 81 base pair rpoB region referred to as the rifampicin-resistance determining region. Also, rifampicin-resistant M. tuberculosis clinical isolates carry multiple mutations in the RNAP genes, particularly rpoA and rpoC, which encode the alpha and beta subunits, respectively. Such secondary mutations offset the fitness cost associated with acquisition of rifampicin-resistance in M. tuberculosis, resulting in resistant strains that are as fit as the wildtype susceptible strains. To analyse the patterns of compensatory mutations in the RNAP genes of rifampicin-resistant M. tuberculosis clinical isolates in Uganda, whole genome sequencing and Sanger DNA sequencing were performed on 52 M. tuberculosis isolates, 20 drug-susceptible and 32 multidrug resistant (MDR). Overall, we found putative compensatory mutations to be prevalent in rifampicin-resistant M. tuberculosis clinical isolates in Uganda, and further studies to determine their association with strain genetic background, fitness and transmission in an endemic setting with a high burden of HIV-TB coinfection, are required.