Whole-genome sequencing of rifampicin-resistant M. tuberculosis strains identifies compensatory mutations in RNA polymerase

Drug-resistant bacteria are emerging worldwide, despite frequently being less fit than drug-susceptible strains(1). Data from model systems suggest the fitness cost of antimicrobial resistance can be mitigated by compensatory mutations(2). However, current evidence that compensatory evolution plays any significant role in the success of drug-resistant bacteria in human populations is weak(3–6). Here we describe a set of novel compensatory mutations in the RNA polymerase of rifampicin-resistant Mycobacterium tuberculosis, the etiologic agent of human tuberculosis (TB). M. tuberculosis strains harbouring these compensatory mutations exhibited a high competitive fitness in vitro. Moreover, these mutations were associated with high in vivo fitness as determined by their relative clinical frequency across patient populations. Importantly, in countries with the world’s highest incidence of multidrug-resistant (MDR) TB(7), more than 30% of MDR clinical isolates had such a mutation. Our findings support a role for compensatory evolution in the global epidemics of MDR-TB(8).