Wednesday, 16 July 2014

Atomic insights into bacterial warfare could help fight against drug-resistant germs

Sylvie Rebuffat (far right) and her team - including (from left) Yanyan Li, Christophe Goulard and Severine Zirah - set out to unlock the molecular puzzle of precisely how lasso peptides work.

Sylvie Rebuffat (far right) and her team - including (from left) Yanyan Li, Christophe Goulard and Severine Zirah - set out to unlock the molecular puzzle of precisely how lasso peptides work.

Scientists are using every trick in the book to go one-up in the global arms race against evolving pathogens.

Earlier this year, the World Health Organisation issued a reality check. Far from an apocalyptic fantasy, antimicrobial resistance is happening now. In every region of the world, resistance to antibiotics has the potential to affect anyone of any age in any country. To quote WHO, the problem is so serious that it threatens to negate the achievements of modern medicine.

In light of the chilling picture painted in its April report, preventing a regression to the dark ages of treating disease should be at the top of our agenda. Nobody wants to go back to when common infections and minor injuries could kill you. And it isn’t just governments and health authorities entering the fray. Scientists, too, are using every trick in the book to go one-up in the global arms race against evolving pathogens.

Sylvie Rebuffat, a professor at the Museum National d’Histoire Naturelle in Paris, will tell you that bacteria do not live isolated lives in nature; they exist in communities. Groups of different bacteria compete for resources within their environment, waging war on one another.

One novel piece of research is looking at the potential of using the “war tactics” bacteria utilise in such situations to humanity’s advantage. Rebuffat specialises in molecular defence and communication within “microbial ecosystems”, and harbours a particular interest in peptides. Peptides are made up of short amino acid chains, and are smaller than proteins.

Generally speaking, peptides are produced by all organisms, and many have antimicrobial properties. This is a fact we have long exploited to our advantage – for example, penicillin is based on an antimicrobial peptide produced by blue mould. In the bacterial context, peptides are thought to be used in molecular signalling, both as a form of communication between bacteria, as well as defence.

Recently, Rebuffat’s research team from the Museum National d’Histoire Naturelle decided to collaborate with scientists from Imperial College London and the University Of Oxford. They had a very specific question in mind: can we exploit the tools of warfare used by bacteria in the human battle against these microscopic pathogens?

Rope 'em up: Studying lasso peptides has given researchers vital clues to fight drug-resistant microbes. – Catherine Pougault/ Museum National d’Histoire Naturelle

Germ Warfare

Lasso peptides are a special category of peptides – identified as such by the way charges on their amino acid chains cause them to fold. Essentially, they look a bit like lassos, a linear tail threaded through a small ring. They are chemically stable, showing resistance to extreme acidity, high temperatures and digestion by proteases, which makes them ideal drug candidates.

Rebuffat and her fellow researchers were interested in a particular lasso peptide called microcin J25, known to exhibit antimicrobial properties. It is produced by bacteria competing for resources and targets receptors found on Escherichia coli, certain variations of which cause food poisoning.

Within human hosts, iron – essential to a variety of bacterial cell processes – is often in short supply. Many species of bacteria have evolved a way around this: they “spit out” little iron-binding compounds called siderophores into their surrounding environment.

These little molecules then mop up traces of iron, bundling them into efficient little complexes, before being reabsorbed via special receptors in the bacterial cell membrane. The receptors recognise the siderophores through special motifs – like a lock and key, without which the gateway back into the cell remains closed.

Microcin J25 lasso peptides exploit that. Camouflaged structurally, they resemble siderophores but work like tiny little Trojan horses. Once inside enemy territory, the microcin J25s hijack certain cell processes, ultimately destroying their target and eliminating the competition.

Cowboy Molecules

Microcin J25 has long been known to be antimicrobial. Rebuffat and her team, however, wanted to unlock the molecular puzzle of precisely how this lasso peptide works. So she left Paris and crossed the Channel, joining an assembly of fellow researchers in possession of complementary expertise – a team led by Dr Konstantinos Beis’ group from Imperial College London and Prof Carol Robinson in England.

Beis’ team grew crystals of the receptor in the presence of the peptide and collected X-ray data at the Diamond Light Source synchrotron facility, which houses one of the most advanced synchrotron machines in the world to gain molecular insights into the puzzle.

They were able to reconstruct a 3D image – an atomic-level visualisation of bacterial battle machinery in action. The most important outcome of this was proof-of-concept about how Microcin J25s work.

“The data allowed us to ‘visualise’ which region of the peptide is important for interactions with the receptor,” Rebuffat explains. “This study opens the path to alternative antibacterials. Bacteria can confer resistance to many common antibiotics, by preventing entry to the cell or chemically deactivating them. Using antibacterials that can hijack essential nutrient pathways will give us an advantage in overcoming the resistance that bacteria have developed.”

The group published its findings in Nature Chemical Biology, in April.

Previous animal studies have shown that microcin J25 holds potential as a bioactive natural product, which could be further enhanced by a semi-synthetic route. It can also be used as a model study.

“Further studies on other membrane receptors should be developed, as other pathogens have different receptors,” Rebuffat adds. The next step, she says, is to design novel lasso peptides or find natural ones through genome mining approaches to see if equivalents exist for receptors in other pathogens. More work also needs to be done on identifying the roles that lasso peptides play in their natural bacterial environments.

This isn’t the end of the road; there is clearly a lot more work to be done. It does, however, mark the start of a promising new path in the battle against increasing antimicrobial resistance – a path already marked out by the war strategies of bacteria. After all, why re-invent the wheel when Mother Nature has already done such a great job?

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Tags / Keywords: Science Technology , microcin J25 , antibiotic , peptides , Imperial College London , Diamond Light Source , Museum National d Histoire Naturelle , University of Oxfor


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