Awakening sleeping antibiotics with ERC Advanced grant

Facilitating the search for new antibiotics: that's what Gilles van Wezel aims to do. The professor of Molecular Biology at Leiden Universiteit's Institute of Biology (IBL) and Honorary Fellow at NIOO wants to look at similarities in the DNA of antibiotic-producing bacteria. For this project, he's just been awarded an Advanced grant from the European Research Council to the tune of 2.5 million euros.

Bacteria are increasingly resistant to existing antibiotics, while fewer and fewer new antibiotics are being developed. "It's a major social problem", says Van Wezel. "I want to add a new dimension to the exploration, so that we can look for new medicines more efficiently."

Van Wezel’s lab works with streptomycetes, a group of bacteria that is responsible for two-thirds of current antibiotics. The antibiotics are derived from natural products that the bacteria excrete in the lab. However, there is a problem: researchers have repeated this method so many times, that they hardly find any new natural products anymore. 

Bringing nature into the lab

Nevertheless, there are still many interesting natural products to be discovered in streptomycetes. "But these only appear when the bacterium receives a certain signal from its surroundings", Van Wezel explains.

These can be factors in nature: drought, the presence of competitors such as fungi or bacteria, or a hormone from a plant with which the streptomycete lives. The only thing that's clear is that they're not signals the bacterium would receive in a laboratory. That's made it hard to pinpoint the exact nature of the signals. But once that's been established, believes Van Wezel, these 'sleeping' antibiotics may be awakened.

Marnix Medema, researcher at Wageningen UR and Leiden University, developed software to look for interesting pieces of DNA in all kinds of streptomycetes. Van Wezel will work with this data. "We now see information for more than a million natural substances. How do researchers know where to start? That's where this project is really going to make a difference."

Similarities in DNA

Van Wezel not only wants to track down the signals, he also wants to know how they're received and ultimately how they turn on the molecular switch. He wants to make those switches visible in the DNA. He's joined in his research by professor Jos Raaijmakers of NIOO-KNAW, where Van Wezel is an honorary fellow.

Together, they want to show that plants can directly control the production of bioactive substances through streptomycetes, and thus influence the switches. The Joint Genome Initiative in Berkeley, USA, will help to map out all these switches, by making an overview of the model organism Streptomyces coelicolor.

In this way, they hope they'll be able to predict what you need to do to trigger antibiotics. Additionally, a large part of the investigated DNA is also preserved in other streptomycetes. And so there, too, it's possible predict what you need to do to wake up a particular antibiotic.

Making the results public

"We do the analyses and predictions, and we'll immediately make these data available for everyone", says Van Wezel, who has called this research project COMMUNITY partly for this reason.

"It's not just about the surroundings in which streptomycetes live in nature, but also about cooperation with the scientific community. We will immediately make our results Open Access. That should result in freer research, and hopefully more collaborations."
 
The results Van Wezel hopes to find are only the first step towards the development of new drugs. "My research will help other researchers to make choices faced with the vast amount of information, and to select candidates among the millions of interesting DNA clusters. They can then develop this further."

Giving pleasure worldwide

"I think this project will help a lot of young people in their research", says an excited Van Wezel. "Instead of spending four years analysing natural substances at random, they can now look specifically at which pieces of DNA are most relevant to their research."

He  considers the ERC Advanced grant welcome recognition. "Because it is probably the most competitive grant in Europe. But however nice it is, I hope above all for valuable discoveries. I think COMMUNITY will give pleasure to many people worldwide."

(Photograph of streptomycetes: Wikimedia Commons)