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How compensatory evolution leads to multi-drug-resistant TB

19 December 2011

Research at NIMR and the Swiss Tropical and Public Health Institute has described a set of compensatory mutations in the RNA polymerase genes 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 M. tuberculosis incurable. Epidemics of drug-resistant bacteria emerge even though resistant strains are often ‘weaker’ than 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. MDR strains of M. tuberculosis are resistant to isoniazid and rifampicin, the two most commonly used and effective drugs for the treatment of TB. Compensatory mechanisms have been identified for fitness defects related to isoniazid resistance but little is known with respect to compensatory evolution in rifampicin-resistant M. tuberculosis.

Rifampicin binds to the bacterial RNA polymerase and inhibits transcription. More than 95% of M. tuberculosis clinical strains that are resistant to rifampicin have a mutation that affects this binding. Laboratory-generated mutants of M. tuberculosis with a rifampicin resistance-conferring mutation have reduced fitness compared to their drug-susceptible ancestors when grown in the absence of rifampicin. By contrast, some M. tuberculosis clinical strains isolated from individuals with TB who developed rifampicin resistance during treatment showed no fitness cost compared to their rifampicin-susceptible counterparts, despite carrying the same mutation as some of the laboratory-derived strains.

Research by Sébastien Gagneux (pictured), at the Swiss Tropical and Public Health Institute (Swiss TPH) and in NIMR’s Division of Mycobacterial Research, has compared the genome sequences of ten paired clinical rifampicin-resistant isolates to the genomes of the corresponding rifampicin-susceptible isolates recovered from the same infected individual at an earlier time point. Comparison of the whole-genome sequences of the in vitro–evolved strains to their respective rifampicin-susceptible ancestors led to identification of putative compensatory mutations, as well as mutations likely to represent adaptations to growth in the laboratory.

M. tuberculosis strains harbouring 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. 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.

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Putative compensatory mutations fall in regions encoding the interface of the RNA polymerase subunits.

These findings support a role for compensatory evolution in the global epidemics of MDR TB. They suggest that the acquisition over time of particular mutations in rifampicin-resistant M. tuberculosis strains leads to the emergence of MDR strains with high fitness. Furthermore, the data show that these mutations occur at high frequencies in clinical settings, particularly in hotspot regions of MDR TB. Use of targeted genotyping of these mutations will enable TB control programs to focus on the most transmissible MDR strains.

Sébastien Gagneux

Sébastien Gagneux was a programme leader at NIMR before moving to the University of Basel in 2010. Much of this work was carried out in his group at NIMR.