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Team Detects Mutations Suspected of Boosting Fitness of Drug-Resistant TB Bacteria

NEW YORK (GenomeWeb News) – Mutations in some RNA polymerase genes can enhance the fitness of drug-resistant forms of tuberculosis-causing bacteria, according to study in the online version of Nature Genetics.

A team from Switzerland, Germany, the US, and the UK sequenced and compared the genomes of Mycobacterium tuberculosis strains that are sensitive or resistant to a drug called rifampicin, identifying mutations in RNA polymerase sub-unit genes rpoA and rpoC that they suspected might help drug resistant strains maintain their fitness — a prediction that appeared to be supported by patterns in multi-drug resistant clinical samples from around the world that were screened for the study.

"[O]ur results suggest that the acquisition over time of particular mutations in rpoA and rpoC in rifampicin-resistant M. tuberculosis strains leads to the emergence of [multi-drug resistant] strains with high fitness," University of Basel and the Swiss Tropical and Public Health Institute researcher Sebastien Gagneux, the study's senior author, and colleagues wrote, adding that mutations in these genes "occur at high frequencies in clinical settings, particularly in hotpot regions of [multi-drug resistant tuberculosis]."

While drug resistance offers tuberculosis-causing bacteria a survival edge, some of the adaptations that produce this resistance can slow M. tuberculosis bacteria growth rates compared to their drug-sensitive counterparts, Gagneux and his co-authors explained.

Even so, they added, there are M. tuberculosis strains that show drug-resistance without a corresponding decline in fitness, though not much is known about the additional genetic changes that help the resistant strains retain their fitness or about the clinical implications of these compensatory mutations.

To look at such questions in more detail, the team used Illumina GA paired-end sequencing to sequence the genomes of M. tuberculosis strains that were sensitive or resistant to rifampicin, a drug that hampers transcription by binding an RNA polymerase sub-unit called RpoB.

In particular, researchers focused on 10 rifampicin-resistant clinical strains with matched, drug-sensitive samples obtained from the same individuals prior to the development of resistance. They also assessed six strains that had been prompted to develop rifampicin resistance in the lab.

Along with mutations in a region previously linked to ripfampicin in rpoB, a gene coding for the RNA polymerase sub-unit bound by the drug, the researchers uncovered more than 50 potential compensatory mutations in dozens of genes. Among them: multiple mutations in genes coding for two other RNA polymerase sub-units, RpoA and RpoC.

"Based on the known interactions between the RoA, RpoB, and RpoC sub-units," they explained, "we reasoned that non-synonymous changes in rpoA and rpoC occurring only in rifampicin-resistant genomes were likely to be compensatory."

When they screened hundreds of rifampicin-sensitive and multi-drug resistant clinical M. tuberculosis samples from around the world, they found mutations in the same RNA polymerase genes in a subset of disease-causing isolates, including roughly a third of drug-resistant isolates from locales with the most pronounced multi-drug resistance rates.

Overall, the findings spurred the study authors to speculate that "the acquisition over time of particular mutations in rpoA and rpoC in rifampicin-resistant M. tuberculosis strains leads to the emergence of [multi-drug resistant] strains with high fitness."

"Additional studies are needed to determine whether [multi-drug resistant] strains of M. tuberculosis with mutations in rpoA and rpoC have increased transmission rates," they added, "and how these mutations contribute to the success of these strains."

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