title: Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes.
abstract: Epidemics of drug-resistant bacteria emerge worldwide, even as resistant strains frequently have reduced fitness compared to their drug-susceptible counterparts. Data from model systems suggest that the fitness cost of antimicrobial resistance can be reduced by compensatory mutations; however, there is limited evidence that compensatory evolution has any significant role in the success of drug-resistant bacteria in human populations. 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, 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.
authors.affiliation: Division of Mycobacterial Research, Medical Research Council, National Institute for Medical Research, London, UK.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Comas
authors.forename: Sonia
authors.initials: S
authors.lastname: Borrell
authors.forename: Andreas
authors.initials: A
authors.lastname: Roetzer
authors.forename: Graham
authors.initials: G
authors.lastname: Rose
authors.forename: Bijaya
authors.initials: B
authors.lastname: Malla
authors.forename: Midori
authors.initials: M
authors.lastname: Kato-Maeda
authors.forename: James
authors.initials: J
authors.lastname: Galagan
authors.forename: Stefan
authors.initials: S
authors.lastname: Niemann
authors.forename: Sebastien
authors.initials: S
authors.lastname: Gagneux
mesh_terms: D012321:DNA-Directed RNA Polymerases / Q000235:genetics*; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D016680:Genome, Bacterial; D008958:Models, Molecular; D009154:Mutation; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000235:genetics*; D012293:Rifampin / Q000494:pharmacology*; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant / Q000453:epidemiology / Q000235:genetics* / Q000382:microbiology
chemical_list: D012321:DNA-Directed RNA Polymerases; D012293:Rifampin