02114nas a2200337   4500000000100000008004100001653003300042653003100075653002200106653002200128653001300150653003100163653001300194653002700207653003800234100001200272700001400284700001400298700001100312700001200323700001700335700001400352700001400366700001400380245014600394856007600540300001100616490000700627520112800634022001401762       2012                            d10aDNA-Directed RNA Polymerases10aDrug Resistance, Bacterial10aGenome, Bacterial10aModels, Molecular10aMutation10aMycobacterium tuberculosis10aRifampin10aSequence Analysis, DNA10aTuberculosis, Multidrug-Resistant1 aComas I1 aBorrell S1 aRoetzer A1 aRose G1 aMalla B1 aKato-Maeda M1 aGalagan J1 aNiemann S1 aGagneux S00aWhole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes.  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246538/pdf/nihms339089.pdf  a106-100 v443 a<p>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.</p>
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