Tuning natural antimicrobials to improve their effectiveness at battling superbugs

August 22, 2011
The truncated endolysin, tagged with Green fluorescent protein, bound to C. difficile. Credit: mage by Kathryn Cross, Imaging Partnership at IFR

Ongoing research at the Institute of Food Research, which is strategically funded by BBSRC, is exploring the use of virus-produced proteins that destroy bacterial cells to combat potentially dangerous microbial infections. Bacteriophages produce endolysin proteins that specifically target certain bacteria, and IFR has been studying one that destroys Clostridium difficile, a common and dangerous source of hospital-acquired infections. New research is showing that it is possible to 'tune' these endolysin properties to increase their effectiveness and aid their development as a new weapon in the battle against superbugs.

Clostridium difficile infection (CDI) is a common and growing problem as a cause of infections, especially in hospitals where the characteristics of the bacteria make it difficult to clear. At the moment, are used to treat infections, but C. difficile is adept at acquiring resistance, meaning the number of effective antibiotics is ever decreasing.

This has driven the search for new , and at IFR Melinda Mayer and Arjan Narbad have been focussing on bacteriophage endolysins. These are relatively short proteins produced by that specifically target certain and then break open the cell walls. They had previously isolated an endolysin, CD27L, which is active against C. difficile when applied externally, but does not affect a large range of other bacteria. This is important as any potential treatment must not affect the native in patients, whose gut microbiota may already have been disturbed.

However, although CD27L works in the laboratory, its activity would probably not be high enough to cope with the vast numbers of C. difficile cells in a growing population in the harsh gut environment to be used as an effective treatment. This prompted the researchers to look more closely at the endolysin.

Endolysins commonly have two domains, one at each end. One domain is thought to be responsible for the specificity of the endolysin, allowing it to bind specifically to wall molecules unique to the bacterial species. This is what was thought to give the endolysin its specific host range. The other catalytic domain attacks the , causing lysis.

They produced shortened versions of the endolysin containing only one of these domains. The truncated CD27L containing only the catalytic domain showed a much higher activity against the C. difficile cells. Surprisingly, however, the truncated endolysin was still inactive on a range of other bacteria, even though the domain thought to make it specific had been removed.

Working with colleagues at the European Molecular Biology Laboratory (EMBL) in Hamburg, the structure of the catalytic domain was solved and used to design mutants to investigate what controls the specificity and activity of the endolysins. The researchers propose that the catalytic domain contributes to the specificity of the endolysin.

In the case of CD27L, binding to the cell wall is not a critical part of the activity of the endolysin, and from these results seems to reduce the activity. This fundamental science on the mode of action of endolysins establishes that in the development of valuable novel therapeutics it may be more appropriate to use truncated versions of endolysins.

More information: Structure-based modification of a Clostridium difficile targeting endolysin affects activity and host range Mayer, M.J. et al Journal of Bacteriology doi:10.1128/JB.00439-11

Related Stories

Recommended for you

Experimental MERS vaccine shows promise in animal studies

July 28, 2015

A two-step regimen of experimental vaccines against Middle East respiratory syndrome (MERS) prompted immune responses in mice and rhesus macaques, report National Institutes of Health scientists who designed the vaccines. ...

Can social isolation fuel epidemics?

July 21, 2015

Conventional wisdom has it that the more people stay within their own social groups and avoid others, the less likely it is small disease outbreaks turn into full-blown epidemics. But the conventional wisdom is wrong, according ...

Lack of knowledge on animal disease leaves humans at risk

July 20, 2015

Researchers from the University of Sydney have painted the most detailed picture to date of major infectious diseases shared between wildlife and livestock, and found a huge gap in knowledge about diseases which could spread ...

IBD genetically similar in Europeans and non-Europeans

July 20, 2015

The first genetic study of inflammatory bowel disease (IBD) to include individuals from diverse populations has shown that the regions of the genome underlying the disease are consistent around the world. This study, conducted ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.