39 new genes implicated in drug-resistant TB identified

An astonishing 39 new genes implicated in drug-resistant tuberculosis have been identified by Harvard researchers, paving way for development of drugs to fight the deadly disease.
For years, physicians around the world have watched as strain after strain of the deadly bacteria Mycobacterium tuberculosis evolves resistance to drugs.
Over the last few decades researchers have used the tools of molecular biology to identify a handful of individual mutations that allow TB to withstand many of the key therapeutics that doctors use to treat it.
These genetic markers serve as clues for new drug development and as tools for diagnosing drug-resistant strains of TB. But the pace of discovery has proven too slow in the face of the complex array of rapidly mutating bacterial strains.

A new method of analysing whole genome sequences of TB, applied to a massive set of strains of the bacteria collected from clinics around the world, has revealed 39 new genes associated with elevated drug resistance.
"We have found that more genes might be implicated in resistance than previously thought, and this means that we can start to unravel the role of these genes," said Megan Murray, HMS professor of global health and social medicine.

"This is significant because it implicates new mechanisms in the evolution of resistance that can be further studied now and raises the possibility of more specific targets for the detection of resistance through molecular methods," said Murray.

These new data suggest that acquiring resistance is a multi-step process, perhaps requiring low-level resistance mutations prior to the ones that are well known.
The findings also suggest that some of these new genes are involved in resistance that may confer "global" resistance traits, helping strains become resistant to a group of antibiotics rather than just one or a single class.
"Several of the genes we identified are related to the bacteria's regulation of cell walls; since many classes of drugs target the cell walls, we speculate that changes to the structure or metabolism of the cell walls might confer resistance to a wide variety of drugs," said first author Maha Farhat.

"Until now, people assumed that single mutations conferred high-level resistance-a strain either had them or did not-but our results challenge that paradigm," Murray said.
The team examined the whole genomes of 116 newly sequenced and 7 previously sequenced strains of TB. The sample included 47 strains with various levels of resistance to a variety of anti-TB drugs, as well as a group of susceptible strains, to allow the researchers to assess the genetic diversity of TB in the wild.
The study was published in Nature Genetics.