Staphylococcus aureus bacteria use chemical signals to coordinate their attacks on human cells, and researchers are designing molecules to jam that communication system. This matters because MRSA and other drug-resistant bacteria kill over 5,000 hospital patients in the UK each year and cost the NHS more than £1 billion annually. New antibiotics are urgently needed, but pharmaceutical companies have been reluctant to develop drugs that bacteria quickly evolve to resist. Rather than trying to kill bacteria directly—which drives resistance—this project targets the signalling system bacteria use to decide when to produce toxins and invade human cells. The researchers have already identified three families of small molecules that can block either the signals, bacterial growth, or both. If successful, this work could produce a new class of infection-fighting drugs that are less likely to provoke resistance because they disarm bacteria rather than kill them. The most promising compounds will be tested in animal infection models, initially against MRSA and then against *Clostridium difficile* and related pathogens. This is primarily fundamental science—understanding the chemical language bacteria speak—but it directly addresses a practical crisis in hospital infection control.
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The emergence, rapid spread and persistence of multi-antibiotic resistant bacteria constitutes a global health threat. The World Health Organization has stated that ?no population is more vulnerable to multi-antibiotic resistance than those admitted to hospital wards?. In the UK, healthcare associated infections account for over 5000 deaths annually and are associated with enormous personal and financial costs to the individual, their family and to the NHS (estimated at over #1 billion p.a.). In this context, both hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA) and Clostridium difficile are particularly problematic. This is not only a consequence of their ability to cause disease but also because antibiotic usage increases resistance and infection rates. Recently new ?community acquired? MRSA strains (CA-MRSA) have emerged which cause invasive infections in healthy young people. Against this backdrop, the development of new classes of antibiotics has lagged far behind the urgent requirement for new drugs, in part because of the reluctance of major pharmaceutical companies to develop expensive new drugs likely to become rapidly obsolete through resistance. Consequently we need to gain better insights into the infection-specific lifestyle of bacteria if we are to discover new ways of preventing and treating infection and reducing the selection of resistant strains. In this project we are seeking to understand how MRSA bacteria use chemical signals to communicate with each to make decisions about when to deploy the armoury of toxins they need to fight off human host defences, grow inside human cells and damage tissues. By understanding the chemical nature of these signals, the way in which they are produced by the bacterial cell and sensed by receptor proteins on the bacterial cell surface we will develop new drug molecules capable of controlling infection by blocking this signalling system. So far we have discovered three different families of small molecules which either inhibit signalling or growth or both. We will therefore use medicinal chemistry and biological approaches to understand how these compounds work at the molecular level and use this information to design agents with increased potency in antibacterial assays in the laboratory. The most promising compounds will be tested for efficacy in experimental animal infection models. The work with focus on primarily MRSA but promising compounds will also be tested against C. difficile and related pathogens.
Alan Cockayne (Co-Investigator)Klaus Winzer (Co-Investigator)Paul Williams (Principal Investigator)Philip Hill (Co-Investigator)Weng Chan (Co-Investigator)
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