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TB genomes yield insights on drug resistance

Source: Fri, 6 Sep 2013 09:55 GMT
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Research on the huge genetic diversity of tuberculosisbacteria and the complex genetics behind growing worldwide resistance to TB drugs could pave the way for improved diagnostic tools to tackle this problem, say researchers.
 
Three independent studies of the TB genome, published in Nature Genetics today, provide insights into how genetic changes, or mutations, confer drug resistance on Mycobacterium tuberculosis. A fourth study looks at how the bacterium accompanied ancient human migration out of Africa and multiplied with increases in human population densities.
 
A study by Maha R. Farhat, a researcher at Harvard Medical School, United States, and colleagues, analysed the genomes of 123 TB strains from around the world that represent the major genetic and drug-resistant groups.
 
They identified new mutations and biochemical pathways that are linked to drug resistance and could be key 'markers' for identifying resistance cases in hours, compared with the days or weeks taken by culture tests that involve growing TB from patient samples.
 
"We hope that these mutations can be used to expand the currently used diagnostic tools that are based on mutation detection," Farhat tellsSciDev.Net.
 
"We also hope that these mutations can expand our understanding of how drug resistance develops, paving the way to better ways of treating drug-resistant TB and even preventing drug resistance from developing."

“The genetic basis of drug resistance is more complex than previously anticipated.”

Lijun Bi et al. in 
Nature Genetics

A team co-led by researcher Lijun Bi of the Institute of Biophysics at the Chinese Academy of Sciences, in Beijing, sequenced the genetic material of 161 TB strains from China, and identified new genetic regions linked to drug resistance.
 
"Our work indicates that the genetic basis of drug resistance is more complex than previously anticipated and provides a strong foundation for elucidating unknown drug resistance mechanisms," the study says.
 
China faces a "particularly acute" problem of TB drug resistance as 5.7 per cent of new cases of the disease are multidrug resistant (MDR) because patients do not respond to the two primary TB drugs isoniazid and rifampicin. Furthermore, eight per cent of MDR cases become extensively drug-resistant, where patients also do not respond to other drugs used to treat MDR cases.
 
A third study, by a team led by David Alland, a researcher from New Jersey Medical School, Rutgers University, United States, shows that the emergence of resistance to one of the first-line TB drugs, ethambutol, is a multistep process, involving changes in and interactions between several genes, which result in a range of resistance levels.
 
"As these mutant strains [with low-level resistance] accumulate, they would constitute a pool from which fully drug-resistant strains could preferentially emerge," their report says.
 
It concludes that current diagnostic tools are inadequate to detect low-level drug resistance, and that diagnostic tests should screen mutations for both low- and high-level resistance.
 
A fourth study, by Iñaki Comas, a researcher at the Centre for Public Health Research in Valencia, Spain, and colleagues, which analysed genomes of 259 strains of tuberculosis, shows how the TB bacterium emerged about 70,000 years ago in Africa, and accompanied human migration out of the continent. It evolved in parallel with its human hosts and expanded each time human population density rose.
 
"We think we are closer to identifying those genetic changes that have allowed the bacteria to adapt to different human populations and that these changes will give us a clue about the modulation of virulence of the bacteria," Comas tells SciDev.Net.
 
"We want to continue working on the application of next-generation sequencing for [use in] improving diagnosis, treatment and public health approaches to tackling tuberculosis," he adds.

Madhukar Pai, an associate director at McGill International TB Centre in Canada, says the results of the studies on drug resistance have two important applications.

"As new diagnostics are being developed for the future, it is most helpful for product developers to know which mutations are critical for identifying resistance to various drugs," he tells SciDev.Net.

Also, "as new TB drugs are being developed, it is helpful to understand when and how resistance can emerge to the newer drugs, so that we can help reduce the risk of losing new drugs quickly".
 
Link to full article by Comas et al. in Nature Genetics

Link to full article by Farhat et al. in Nature Genetics

Link to full article by Bi et al. in Nature Genetics

Link to full article by Alland et al. in Nature Genetics

References

Nature Genetics doi: 10.1038/ng.2747 (2013)
Nature Genetics doi: 10.1038/ng.2735 (2013)
Nature Genetics doi: 10.1038/ng.2743 (2013)
Nature Genetics doi: 10.1038/ng.2744 (2013)

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