UK scientists aim to target harmful bacteria by interrupting their communication.

Most antibiotics inhibit processes essential for bacteria to live. This establishes a selection pressure that means only the hardiest strains survive. The resulting increase in antibiotic resistance has led scientists to seek alternative ways to treat bacterial infection. One of these, says David Spring from the University of Cambridge, is to hinder interactions between bacteria. 

'An intercellular signalling mechanism called quorum sensing regulates processes associated with virulence - the nasty things bacteria do to a host,' explains Spring. By disrupting this process, he adds, scientists could prevent bacteria from harming their host, but without killing them and causing drug resistance. 

In many bacteria, quorum sensing is mediated by N-acylated-L-homoserine lactones (AHLs). With the aim of eventually disrupting the AHL dependent process, Spring and colleagues have designed analogues of the transition state in AHL ring hydrolysis - a reaction that deactivates the signalling compounds. 

Communication breakdown: transition state analogues such as Spring's sulfone could lead to a new method to treat bacterial infections

The idea is that analogues that resemble a transition state will bind well to antibodies that catalyse the corresponding reaction. In this way they could be used to select the most active antibodies from a library. Spring explains that in previous work, molecules have not been specifically designed to mimic the AHL hydrolysis transition state, and the corresponding antibodies showed only moderate activity. The researchers have shown that one of their analogues inhibited an AHL hydrolase, suggesting it is a good transition state mimic that could be used to select antibodies for the hydrolysis.

Gregory Challis, whose research at the University of Warwick, Coventry, UK, covers both the bacterial and antibiotic fields, says that one of the challenges facing the researchers will be to test the antibodies selected by the mimic in AHL hydrolysis. Spring already has plans to tackle this, intending to first test the catalytic activity on small molecules before moving on to in vivo studies to test the effectiveness against bacterial communication.

'There is encouraging evidence that this is a viable way forward,' says Spring. 'Quorum sensing inhibitors have been shown to dramatically increase the survival of mice infected with Pseudomonas aeruginosa, which kills many immunosuppressed humans every year.' He says this work may lead directly to the development of 'a crucially needed new method for the treatment of human bacterial infections.'

Rachel Cooper

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