Tuberculosis: Nature has a double-duty antibiotic up her sleeve

December 3, 2013

Technology has made it possible to synthesize increasingly targeted drugs. But scientists still have much to learn from Mother Nature. Pyridomycin, a substance produced by non-pathogenic soil bacteria, has been found to be a potent antibiotic against a related strain of bacteria that cause tuberculosis. The EPFL scientists who discovered this unexpected property now have a better understanding of how the molecule functions. Its complex three-dimensional structure allows it to act simultaneously on two parts of a key enzyme in the tuberculosis bacillus, and in doing so, dramatically reduce the risk that the bacteria will develop multiple resistances.

The researchers, along with their colleagues at ETH Zurich, have published their results in the journal Nature Chemical Biology.

Stewart Cole, director of EPFL's Global Health Institute, led a team that discovered the anti- effect of pyridomycin in 2012. By inhibiting the action of the "InhA" enzyme, pyridomycin literally caused the thick lipid membrane of the bacterium to burst. Now the scientists understand how the molecule does this job.

Dual anti-mutation ability

The tuberculosis bacillus needs the InhA enzyme along with what scientists refer to as a "co-factor," which activates the enzyme, in order to manufacture its membrane. The scientists discovered that pyridomycin binds with the co-factor, neutralizing it.

But pyridomycin doesn't stop there. It also blocks another element needed for making the membrane, the InhA binding site. "Researchers in the pharmaceutical industry have been looking for this weakness in the TB bacillus for decades," explains Ruben Hartkoorn, first author on the article.

By binding simultaneously onto these two elements and neutralizing them, pyridomycin prevents the bacterium from generating its membrane, and it ends up bursting like a balloon. Better still, this dual action drastically reduces the risk that the bacteria will become resistant, because in order to develop resistance, two different specific mutations must exist at the same time. This is increasingly important because cases of multi-resistant TB are on the rise.

Nature's twisting paths – a lesson in efficiency

"It's a powerful lesson from nature with respect to drug design," explains Cole, co-author and EPFL professor. "The three-dimensional structures of naturally occurring molecules are often more complex, more twisted, than synthetic molecules, and that's precisely what allows pyridomycin to bind onto these two sites simultaneously."

In fact, it binds so effectively that the molecule is not yet ready to be used therapeutically: it doesn't last long enough in the patient's body. This is the point at which bioengineering needs to take over from Mother Nature – to develop a more robust version of the molecule. This is what the ETH team led by Karl-Heinz Altmann is working on. "Eventually we could multiply the molecule's binding sites, so that it could inhibit critical functions of other pathogenic bacteria," says Cole.

Explore further: Scientists reveal how natural antibiotic kills tuberculosis bacterium

Related Stories

A new target in the fight against TB

July 8, 2013

(Medical Xpress)—Researchers have identified a potential new route for attacking tuberculosis that may hold promise against drug-resistant strains of the disease and even dormant TB infections.

New strategy in the fight against TB?

October 2, 2013

A new approach to combating the tubercle bacillus, the microorganism that kills some 1.5 million people in the world each year, has been developed by a French-British team including scientists from CNRS, Inserm, the Institut ...

Recommended for you

Zika virus infection alters human and viral RNA

October 20, 2016

Researchers at University of California San Diego School of Medicine have discovered that Zika virus infection leads to modifications of both viral and human genetic material. These modifications—chemical tags known as ...

Food-poisoning bacteria may be behind Crohn's disease

October 19, 2016

People who retain a particular bacterium in their gut after a bout of food poisoning may be at an increased risk of developing Crohn's disease later in life, according to a new study led by researchers at McMaster University.

Neurodevelopmental model of Zika may provide rapid answers

October 19, 2016

A newly published study from researchers working in collaboration with the Regenerative Bioscience Center at the University of Georgia demonstrates fetal death and brain damage in early chick embryos similar to microcephaly—a ...

Scientists uncover new facets of Zika-related birth defects

October 17, 2016

In a study that could one day help eliminate the tragic birth defects caused by Zika virus, scientists from the Florida campus of The Scripps Research Institute (TSRI) have elucidated how the virus attacks the brains of newborns, ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.