New antibiotics a step closer with discovery of bacterial protein structure

Scientists have uncovered the structure of the protein complex that assembles the tiny hair-like strands that cover the outside of bacteria. Called pili, these 'hairs' allow bacteria to group together and stick to human cells to cause infection - and are therefore a key target for a new generation of antibiotics.

Published today in Nature, scientists at the Institute of Structural and Molecular Biology (a joint institute between University College London (UCL) and Birkbeck) have revealed the structure of a complex protein called FimD that acts as an assembly platform for the pili of cystitis bacteria. The structure of the FimD protein means scientists can see the process of pili assembly, from individual protein subunits to complete structures, for the first time.

Pili are tiny hair-like strands on the outside of bacteria that help them to link together in groups. In the case of cystitis, pili allow bacteria to attach themselves to the wall of the bladder, leading to bladder cells engulfing the bacterium. Once the bacteria have invaded the bladder cells, they escape traditional antibiotic treatment and lie dormant, making recurrent infections very common.

Scientists believe that antibiotics could be developed that disrupt the FimD protein, and therefore the production line of pili proteins. The UCL/Birkbeck group, together with collaborators in the USA, have already discovered small molecules able to interfere with pilus biogenesis. Without their pili, bacteria cannot attach to each other or the host, making infection much less likely.

Professor Gabriel Waksman from the UCL Research Department of Structural and Molecular Biology and the Birkbeck Department of Biological Sciences, who led the research, said: "Cystitis is one of the most common gram negative bacterial infections; it can also be extremely painful and surprisingly hard to treat – especially repeat infections."

"Pili are a prime target for a new breed of antibiotics to target cystitis and other conditions, as without pili bacteria are unable to attach themselves to each other or the walls of human cells, and therefore much less likely to cause serious infections."

Pili protein subunits are made inside bacteria and initially transported through the inner cell wall. Each subunit is then picked up by a 'chaperone' protein which takes it across to a protein in the outer cell wall called the 'usher'.

The usher protein coordinates the ordered assembly of pilus subunits, i.e. the growth of the pili. This research, funded by the Medical Research Council, has isolated and crystallised the usher protein in cystitis bacteria, FimD, while it's bound to the chaperone/subunit combination.

The structure of FimD provides insights into pilus biogenesis because it unravels the entire mechanism of subunit polymerization and transport across the outer wall of the bacteria. "Scientists have been working for a number of years to work out the how pili are assembled. This is the first view of the transportation and assembly of pili in action," said Professor Waksman.

1. For more information or to interview Prof Gabriel Waksman, please contact Clare Ryan in the UCL Media Relations Office on tel: +44 (0)20 3108 3846, mobile: +44 07747 565 056, out of hours +44 (0)7917 271 364, e-mail: clare.ryan@ucl.ac.uk.

2. 'Crystal structure of the FimD usher bound to its cognate FimC:FimH substrate' is published online in Nature today. Journalists can obtain copies of the paper by contacting UCL Media Relations.

3. An image of the FimD usher protein is available to journalists from UCL Media Relations.

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For almost 100 years the Medical Research Council has improved the health of people in the UK and around the world by supporting the highest quality science. The MRC invests in world-class scientists. It has produced 29 Nobel Prize winners and sustains a flourishing environment for internationally recognised research. The MRC focuses on making an impact and provides the financial muscle and scientific expertise behind medical breakthroughs, including one of the first antibiotics penicillin, the structure of DNA and the lethal link between smoking and cancer. Today MRC funded scientists tackle research into the major health challenges of the 21st century. www.mrc.ac.uk