TB genomes yield insights on drug resistance
Research on the huge genetic diversity of tuberculosis bacteria 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 tells SciDev.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." 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
Source:
SciDev.net
