But many of the regions that the teams identified have unclear roles. “For around half the genes in our list, we have a name but we don’t know what they do,” says Murray. For example, her list includes 16 genes from the PE/PPE family, which are unique to M. tuberculosis and its kin, and whose roles are largely unknown.
William Jacobs, Jr., a tuberculosis specialist at the Albert Einstein College of Medicine in New York, says that the teams now need to validate their lists. “You’ve got to be able to move the mutation, and show it causes what you think it causes,” he says.
Murray’s group made a start by introducing a mutation in the ponA1 gene into M. tuberculosis, and showing that the microbes could then withstand double the dose of rifampicin. “That’ll need to happen on a much larger scale for all of these genes,” she says.
These latest studies show that M. tuberculosis evolves resistance through several gradual steps with subtle effects. “It probably takes a bunch of these smaller steps to get to high-level resistance,” says Murray. David Alland of Rutgers University, supports this view through a third study, also published in Nature Genetics. His team sequenced 63 clinical samples of M. tuberculosis that had been exposed to the frontline drug ethambutol. They found mutations in at least four genes that interacted to improve the bacterium’s ability to resist the drug, allowing some strains to shrug off 16-fold higher doses than others.
Understanding these step-wise pathways could help clinicians to monitor strains that are on the verge of evolving high-level resistance, or develop drugs that interfere with that evolution before it really gets going.
"This is a bit of a dream, really, since we are not at the point of developing TB drugs for specific targets. It's rather more hit and miss," says Helen Cox, an epidemiologist at the non-governmental organization Médecins Sans Frontières (also known as Doctors Without Borders), headquartered in Geneva, Switzerland. But, she adds, "The overarching message is that drug resistance is much more complex than the simple dichotomous 'resistant versus susceptible' understanding."
This article is reproduced with permission from the magazine Nature. The article was first published on September 1, 2013.