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Tool to measure TB drug resistance

New Delhi, Feb. 6: Indian scientists, using genetic tricks to make bacteria glow green, have developed what they say is the world’s first tool to measure a tuberculosis microbe’s ability to survive antibiotics and speed up the search for new anti-TB drugs.

The researchers say their tool has also revealed a previously unknown phenomenon in biology that may explain why TB infections are so difficult to treat — genetically similar TB bacteria lurking in human cells may respond quite differently to antibiotics.

Biologist Amit Singh and his colleagues at the International Centre for Genetic Engineering and Biotechnology (ICGEB), New Delhi, have developed a novel protein-based biosensor, a tool to measure a key chemical signature of an individual TB bacterium.

The biosensor allows researchers to quantify the capacity of TB bacteria to survive antibiotics through an anti-oxidant substance called mycothiol that these microbes produce to protect themselves from being killed by the drugs.

“We have the first precise measurements of this anti-oxidant produced by an individual TB bacterium,” said Singh, the principal investigator of the study supported by India’s department of biotechnology and the UK-based Wellcome Trust.

The findings, just published in the international journal PLOS Pathogens, may also explain how a small population of drug-tolerant TB bacteria can survive in cells called macrophages in patients infected with TB for months even when they are taking anti-TB medications.

The study has also suggested that antibiotics work in harmony with the body’s own macrophages to kill TB bacteria. This observation puts a question mark on the reliability of present-day drug screening tests routinely used to determine which specific antibiotics can kill a population of TB microbes.

In virtually all existing drug screening tests, researchers pour chemical compounds onto colonies of TB microbes in test tubes. The new findings suggest that it would be far more reliable to screen drugs on TB-infected macrophages than inside test tubes.

“This is a fantastic study that elegantly invokes two major ideas with implications for anti-TB drug therapy,” said Maziar Divangahi, assistant professor of medicine at McGill University in Canada, who specialises in TB and immunology but was not associated with the ICGEB study.

“We need to seriously re-evaluate our anti-TB drug screening strategy, which is to directly dump the candidate drug on the bacteria without considering macrophages, the natural host of TB bacteria,” Divangahi said.

In the ICGEB experiments, Ashima Bhaskar, a post-doctoral scientist and other research scholars genetically engineered TB bacteria to make them express a green-coloured protein that serves as a biosensor for the anti-oxidant mycothiol. “The changes in the intensity of the green colour allow us to monitor variations in the mycothiol levels at the level of a single TB bacterium,” Bhaskar said.

A senior scientist said the study’s demonstration that genetically similar bacteria behave differently inside macrophages, which in turn determines their susceptibility to antibiotics, was a major “conceptual advance” in TB research.

“With this realisation, screens of anti-TB drugs in the future should move from test tubes to infected macrophages,” said Shahid Jameel, chief executive officer of the Wellcome Trust- DBT India Alliance, a public trust that funded the study. “Such macrophage-based screens will hopefully lead to drugs from which the TB bacteria cannot escape,” Jameel said.

“This tool for the first time shows a way to distinguish between genetically similar, but physiologically different, drug-sensitive and drug-tolerant bacteria. This biosensor could eventually lead to a diagnostic test to detect drug-resistant TB,” Singh said.

Public health experts estimate that nearly two billion people worldwide are infected with TB bacteria, although the majority have dormant infections with no symptoms. But about 1.4 million people die from the infection each year.

The infection is currently treated with a set of four standard first-line antibiotics that need to be taken by patients for periods of six months to a year. But patients with drug-resistant TB need to be treated with another set of antibiotics that are expensive and have worse side effects than the first-line drugs.