Bacteria 'bricklayer' protein set for attack

 

Scientists have found a new route to attack antibiotic-resistant bacteria by blocking the mechanism they use to build their exterior coating.

The bugs construct this defensive barrier in a complex process that depends on a key dual-protein molecule.

Its structure has been mapped using the intense X-rays of the Diamond Light Source in Oxfordshire.

Researchers tell the journal Nature that drugs can now be developed to interfere with this LptDE protein.

"We identified how LptDE builds up the outer membrane," explained Prof Changjiang Dong, from the University of East Anglia's Norwich Medical School.

"It does this through a 'path' and a 'gate', and we have shown that if we block the path or the gate, the bacteria will die. To do this, you would design and use another, much smaller molecule," he told BBC News.

The experiments targeted gram-negative bacteria, which cause a large number of infections, ranging from salmonella to meningitis.

This class of bugs is getting increasingly smart at warding off attack from antibiotic treatments thanks in part to the impermeability of its lipid-based outer coating.

The protein complex LptDE is the "bricklayer" that pulls up the lipopolysaccharide "bricks" from inside the bacterium to insert them in the cell wall. 

Crystalline forms of the complex were sent to the Diamond synchrotron, which uses especially brilliant X-rays to illuminate structures at the atomic scale.

The team used this information to then model LptDE's behaviour and determine its weaknesses.

What makes LptDE such a fascinating target for new drugs is that it is highly "conserved" - its role is common across gram-negative bacteria.

 

What is more, by attacking the functioning of the outer membrane new drugs would not need to get inside the bugs before starting their work.

And, in any case, resistant bugs seem to have evolved a mechanism to simply pump antibiotics back out when they do get through.

"If the bacteria do not have the outer membrane, they cannot withstand environmental changes. It also makes it easier for the human immune system to kill them," said Prof Dong.

Prof Mark Fielder, from the Society for Applied Microbiology, commented: "The work reported is at a very early stage but does offer some potentially useful information in the fight against bacterial resistance.

"What is needed now is the development of a usable inhibitor that can be tested against gram-negative clinical strains of bacteria to see if there is a longer term value to the research," he told the Science Media Centre.

And Prof Brendan Wren, from the London School of Hygiene & Tropical Medicine, added: "New antibiotics against gram-negative bacteria, including many hospital superbugs, are notoriously difficult to develop and the problem is exacerbated as many of these bacteria are increasingly resistant to currently used antibiotics.

"The authors have unravelled the structure, architecture and mechanism of transport of a critical surface structure in gram-negative bacteria named the lipopolysaccharide. The studies open new avenues to design a novel class of antibiotics to disarm and kill pathogenic bacteria."

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