Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes

Sebastien Gagneux and colleagues identify a set of compensatory mutations in the RNA polymerase of rifampicin-resistant M. tuberculosis by comparing the whole-genome sequences of ten paired clinical isolates and strains evolved in vitro . These mutations are associated with high competitive fitness in vitro and occur with increased clinical frequency in affected populations with a high burden of drug-resistant tuberculosis. Epidemics of drug-resistant bacteria emerge worldwide, even as resistant strains frequently have reduced fitness compared to their drug-susceptible counterparts 1 . Data from model systems suggest that the fitness cost of antimicrobial resistance can be reduced by compensatory mutations 2 ; however, there is limited evidence that compensatory evolution has any significant role in the success of drug-resistant bacteria in human populations 3 , 4 , 5 , 6 . Here we describe a set of compensatory mutations in the RNA polymerase genes of rifampicin-resistant M. tuberculosis , the etiologic agent of human tuberculosis (TB). M. tuberculosis strains harboring these compensatory mutations showed a high competitive fitness in vitro . Moreover, these mutations were associated with high fitness in vivo , as determined by examining their relative clinical frequency across patient populations. Of note, in countries with the world's highest incidence of multidrug-resistant (MDR) TB 7 , more than 30% of MDR clinical isolates had this form of mutation. Our findings support a role for compensatory evolution in the global epidemics of MDR TB 8 .