Getting the measure of bacterial defences

With superbugs on the rise, scientists are racing to find new ways to fight back. Now microbiologist Chris Whitfield at the University of Guelph and collaborators in the UK may have provided a strategy for how to weaken bacteria’s spiky armour. Their findings were published in Nature Structural & Molecular Biology in December. “This work has given us a great model for what has until now been a puzzle,” says microbiologist Peter Reeves at the University of Sydney.

To keep antibacterial weaponry known as “complement proteins” which punch holes in cells at a safe distance, the bacterium E. coli sports an armour of densely packed spiky sugar chains called O-antigens. The spikes are produced inside the bacterial cell and then flipped to the exterior. The bacteria have a 20-minute division cycle, with each cell donning up to 70,000 sugar chains, so the spikes have to be produced quickly.

“Bacteria are highly efficient and don’t waste energy,” says Whitfield. This production line has exacting standards. If chains are too long they get snagged before the flip; too short and complement proteins penetrate the armour, punching fatal holes into the bacterial cell walls.

So Whitfield and his colleagues set out to find how the quality control works. They knew the production line was powered by two protein workers – one links sugars together to extend the chains while the other caps the chains when they reach the right length. But how does the capper know how long the chains should be? To find out, the scientists bombarded it with high intensity X-rays. Detectors picked up the scattered X-rays that bounced off and formed a 3D snapshot. To the researchers’ amazement, the protein carried its own yardstick – a sturdy 20 nanometre-long coil (a nanometre is a billionth of a metre).

In much the same way as a tailor uses a ruler to measure and cut fabric to size, scientists suspected the coil is used to measure the length of the growing sugar chains. It was an idea first proposed in the 1990s but it needed the high intensity beams produced by a synchrotron to be observed. The synchrotron uses an X-ray scattering technique which allows the shape of proteins to be better understood.

“Physics technologies are giving biology superpowers to rediscover itself,” says David Aragao, a crystallographer at the Australian Synchrotron.

The scientists tested the ruler theory by modifying the part of the gene that codes for the yardstick, making it shorter or longer. Indeed, the sugar chains followed suit, ending up shorter or longer.

Having shed light on the intricate workings of a bacterial sugar spike factory, “this opens up a new avenue of research whereby we can look to design drugs that interfere with the ruler,” says James Naismith of the University of St Andrews and co-author of the study. Without their barbed sugar coat, such bacteria are easy targets for the body’s immune defence.