SWITZERLAND - Research at Swiss TPH has discovered a set of compensatory mutations in the RNA polymerase of rifampicin-resistant M. tuberculosis.

The research is published in Nature Genetics.

The worldwide emergence of multiple-drug resistant (MDR) strains is threatening to make tuberculosis (TB) incurable. Epidemics of drug-resistant bacteria emerge even though resistant strains are often ‘weaker’ than their drug-susceptible counterparts. Research by Sébastien Gagneux and colleagues has compared the genome sequences of paired clinical rifampicin-resistant isolates to the genomes of the corresponding rifampicin-susceptible isolates recovered from the same infected individual. They also analyzed the genomes of in vitro - evolved strains, and identified a set of putative compensatory mutations in the RNA polymerase. M. tuberculosis strains harbouring these 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. In countries with the world’s highest incidence of MDR-TB, more than 30% of MDR clinical isolates had this form of mutation.

These results support a role for compensatory evolution in the global epidemics of MDR- TB. Based on these findings, control measures will be able to target drug-resistant strains of M. tuberculosis with an increased propensity to spread.