Making molecules to fight tuberculosis

A consortium of four research groups, including the group of University of Groningen Professor of Bio-organic Chemistry Adri Minnaard, has received a grant of USD 3.5 million from the Bill and Melinda Gates Foundation to develop a vaccine against tuberculosis. The project will start in Groningen, where Minnaard’s group will synthesize four crucial molecules.

The consortium will go through the whole process of developing a vaccine against Mycobacterium tuberculosis, the tough bug that causes tuberculosis or TB. And that process will start in Groningen with the synthesis of four different molecules that can activate the human immune system. ‘We’re probably the only group in the world that can produce sufficient quantities of them quickly enough’, says Minnaard.

‘There is currently no good vaccine against tuberculosis’, Minnaard explains. The standard approach of using inactivated bacteria as a vaccine elicits an extreme and potentially dangerous response in people. Nor is the second option, using an attenuated bacterium, effective. ‘If you grow M. tuberculosis in the lab for a few generations, it loses most immunogenic molecules.’

It was discovered some fifteen years ago that mammals, including humans, have a special immune system to deal with Mycobacteria, the CD1 system . When a TB infection occurs, this system recognizes several molecules from the bacterial cell wall and presents them to the immune system, which then starts to respond.

‘This response is usually enough to suppress the infection, but not strong enough to kill all the bacteria’, says Minnaard. The infection therefore remains dormant but may flare up if the health of the infected person deteriorates, for example due to aids, hunger or old age. ‘Our vaccine should activate this system before an infection occurs, so that it is strong enough to kill all the invading Mycobacteria.’ This project is the first to attempt to develop a vaccine that works by activating the CD1 system.

The first important step in the development of the new vaccine is to find those molecules of the bacterium that start an immune response. ‘In order to be able to do this we need these molecules in a very pure form, without other compounds that may disrupt our research.’ This rules out purifying them from whole TB bacteria, because this always leaves some residual contaminants.

‘That is how we got involved. Our group is currently the only one in the world that can produce the four different molecules that are required in a reasonable time frame.’ In fact, Minnaard’s group has already produced all four of them at some point. ‘But in minute quantities, just a few milligrams. We need to scale up the production significantly for the experiments that the other research groups in the consortium want to do, such as testing them on animals.’

The four molecules belong to the glycolipids, large molecules that contain a lipid and a carbohydrate. ‘They are very complex, and some ten years ago it would have been impossible to synthesize them’, says Minnaard. But a number of developments in synthetic organic chemistry have now made it possible. New catalysts help control and speed up the synthetic process, because they now allow chemists to take bigger steps during the process.

Minnaard has worked on TB glycolipids since 2006. Why has he been successful in synthesizing them? ‘We at the University of Groningen are very good at stereoselective synthesis.’ Stereoselectivity means that there are two variants of a particular molecule that are the mirror image of each other, like a left and a right hand. Normal chemical synthesis results in equal amounts of both variants. ‘But the biology of these mirror images can be totally different.’ The challenge therefore is to produce only the required ‘hand’. ‘And we in Groningen are the experts in this.’

Four postdocs will spend the next eighteen months making the four different glycolipids of Mycobacterium tuberculosis. The material will then be tested on guinea pigs. ‘Their CD1 system is closest to the human one.’

The total duration of the project is three years, which means quite some pressure on Minnaard’s group to deliver in time. ‘It is a challenge, but we are confident we can pull it off.’ As a synthetic chemist, he is excited to be involved in this applied project. ‘It shows how important synthetic chemistry is in drug development. New treatments aren’t just developed in hospitals, but also in chemistry labs.’

See for more information on the project the Stratingh Institute voor Chemistry website.

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