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

Lausanne, Switzerland, 11 December 2013

Sanofi Pasteur
Creative Commons/Sanofi Pasteur

A natural antibiotic turns out to be a lethal weapon in the fight against tuberculosis. Scientists have discovered it has an unexpected dual action that dramatically reduces the probability that TB bacteria will become resistant.

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.

Prof. Stewart Cole, director of the Global Health Institute (at the EPFL School of Life Sciences), led a team that discovered the anti- tuberculosis 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 Stewart 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.

Source: EPFL

Sixth MM4TB Consortium Meeting

Lille, France, 4 - 5 July 2013

The sixth Consortium Meeting (CM6) was hosted by Dr Priscille Brodin at the Institute Pasteur in Lille, France on 4 - 5 July 2013. The full Scientific Advisory board also attended in order to assess progress.

MM4TB Lille 2012
MM4TB researchers at Lille, France, July 2012

Prof. Valerie Mizrahi Winner of the 2013 Christophe Mérieux Prize

Paris, France, 5 June 2013

Valerie Mizrahi

Prof. Valerie Mizrahi was awarded the 2013 Christophe Mérieux Prize on 5 June in a ceremony at the Institut de France.

Director of the Institute of Infectious Disease and Molecular Medicine and professor at the University of Cape Town in South Africa, she is recognized for her research work in the field of tuberculosis and also for her engagement in developing research on the disease in Africa.

Created to support infectious disease research in developing countries, the Christophe Mérieux Prize is awarded each year by the Fondation Christophe et Rodolphe Mérieux under the auspices of the Institut de France.

Winners receive € 500 000.

Source: Fondation Mérieux

SwissTB Award 2013 joint winner is MM4TB's Ruben C. Hartkoorn

Lausanne, Switzerland, 23 March 2013

Ruben Hartkoorn
Ruben Hartkoorn

For twelve years the Swiss Foundation for Tuberculosis Research, SwissTB, has awarded annually a prize of CHF 10'000 for a research project in the field of tuberculosis. The SwissTB Award 2013 goes one side to the basic researcher Ruben C. Hartkoorn of the EPFL's Global Health Institute, on the other side to the clinical researcher Lukas Fenner from the University of Bern. These two research projects are an important contribution to better understanding - in order to better fight - TB that is still on the rise worldwide.

New research in the fight against tuberculosis

"We had numerous top submissions for the SwissTB-Award 2013", says Dr. Otto Brändli, president of the Swiss Foundation for Tuberculosis Research SwissTB. "The choice has not been easy for us. In the end, we decided to split the prize money and to take into consideration a project from basic research on one hand and a project from clinical research on the other". Thus, both Ruben C. Hartkoorn of the GHI and Luke Fenner from the Institute of Social and Preventive Medicine of the University of Bern have been recognized with the award. The award ceremony will be held on this year's World TB Day in the context of the TB-Symposium of the Swiss Lung Foundation in MŸnchenwiler.

Promising drug approach

The pharmacologist Dr. Ruben C. Hartkoorn has been working for several years as a post-doctoral researcher in the team of microbiologist Prof. Stewart Cole at the EPFL. "Since my childhood in sub-Saharan Africa I have been interested in studing tuberculosis, which is on the rise again in the world, also in its multi-and extensively drug-resistant forms", explains Hartkoorn for the motivation behind his work. This work deals with the study of a non-cytotoxic substances that is effective against the causative agent of tuberculosis, Mycobacterium tuberculosis. The now awarded research shows the effect of the naturally occurring substance Pyridomycin in combating tuberculosis. Pyridomycin is produced by a soil bacterium and like isoniazid, a present day main drug against tuberculosis, pyridomycin acts by inhibiting the production of critical components of the tuberculosis cell wall.

As Hartkoorn and his team were able to demonstrate, the use of Pyridomycin as opposed to Isoniazid has a decisive advantage: it needs no specific activation by the tuberculosis pathogen, and is thus active against strains that are resistant to Isoniazid. "With our research we have gained an important insights into how to develop new drugs against tuberculosis - particularly against isoniazid resistant strains", says pharmacologist Hartkoorn on the relevance of his research.

Source: SwissTB press release

Fifth MM4TB Consortium Meeting

Zaragoza, Spain, 6 - 7 January 2013

The fifth Consortium Meeting (CM) was hosted by Dr José A. Aínsa at Zaragoza in Spain on 10 - 11 January 2013.

Stewart Cole and Jose A Ainsa
Prof. Stewart T. Cole FRS (Scientific coordinator) and Dr José A. AÍnsa (University of Zaragoza) at a Press Conference at Zaragoza, Aragon, Spain on 7 July 2013