It is never a good time to come down with tuberculosis, but in recent years the outlook has become worse.
Resistant strains of tuberculosis are on the rise, limiting treatment options despite decades of antibiotic research. In 2010, at least 650,000 cases of the disease were resistant to the two most effective frontline antibiotics, and in 2012, totally resistant and effectively untreatable strains of Mycobacterium tuberculosis—the bacterium behind the disease—were detected in India.
Now, two teams of scientists have published large catalogues of the mutations that confer resistance on M. tuberculosis after sequencing the complete genomes of hundreds of samples. Their studies, both published in Nature Genetics, greatly increase our understanding of the ways in which this long-term nemesis evades our most potent drugs. (Scientific American is part of Nature Publishing Group.)
“The biggest bottleneck to managing drug-resistant tuberculosis is the delay between suspecting it and confirming it,” says epidemiologist Megan Murray at the Harvard School of Public Health in Boston, Massachusetts, who co-led one of the studies. With a more complete list of resistance mutations, physicians could avoid giving patients drugs that will not help them, while quickly prescribing more appropriate treatments.
Murray’s team sequenced 123 strains from a worldwide collection and mapped the sequences on to an evolutionary tree. They then searched for mutations that were independently linked to resistance across different branches. They identified every part of the M. tuberculosis genome that was already linked to resistance, along with 39 new mutations.
The second team, led by Lijun Bi from the Institute of Biophysics in Beijing, part of the Chinese Academy of Sciences, sequenced 161 samples from Chinese patients and analysed them using a similar method. They identified 84 genes and 32 other regions that were strongly associated with drug resistance.
The two lists have few overlaps, probably because the teams used slightly different methods and studied strains that had evolved resistance from different genetic starting points. “However, the overall message is similar,” says Murray. “A lot more genes are implicated in the development of resistance than we thought, and we don’t really know what they do. There are a lot of ways for the organism to become resistant.”
In the classical view of resistance, M. tuberculosis picks up mutations in enzymes that either activate drugs or are targeted by them. “We’ve been stuck in this mould for too long,” says Robin Warren, a TB specialist from Stellenbosch University in South Africa and a co-author on Murray’s paper. “These new studies show that there’s much greater complexity to resistance than we dreamed of.”
Many of the resistance regions identified in both studies affect the waxy cell wall that surrounds M. tuberculosis cells. Some change its structure, or alter its permeability. Others influence the production of molecular pumps that evict drugs that get into the cells. And others boost the rate at which M. tuberculosis mutates, allowing it to pick up beneficial mutations more quickly.
The teams also identified mutations that are likely to influence other resistance genes, either boosting their activity or compensating for their detrimental effects, allowing the bacteria to carry them without being outcompeted by drug-sensitive strains.