New antibacterials being developed to tackle MRSA superbug
15 January 2007
A novel antibacterial medicine that kills the superbug MRSA is being developed under a new scheme launched by the Wellcome Trust. The Seeding Drug Discovery initiative is aimed at catalysing the development of new drugs in areas of unmet need.
Prolysis, an R&D company based in Oxford, has received one of three inaugural Seeding Drug Discovery awards for its new antibacterial compounds aimed at tackling life-threatening, drug-resistant infections caused by staphylococci, including MRSA.
The bacterium Staphylococcus aureus can infect wounds, including those resulting from medical procedures conducted in hospitals. It may then spread further into the body and cause serious infections such as blood poisoning. Methicillin-resistant Staphylococcus aureus, or MRSA, is a form of the bacterium that is resistant to the drug methicillin and a number of other antibiotics, and tends to be more difficult to treat.
"The so-called superbug MRSA is fast becoming untreatable with the currently available antibiotics," says Dr Ted Bianco, Director of Technology Transfer at the Wellcome Trust. "We urgently need a new generation of antibacterial medicines to stop its spread through hospitals, nursing homes and the wider community."
The compounds being developed by Prolysis under the award from the Wellcome Trust block the ability of the MRSA bacteria to divide and multiply. They do this by inhibiting the function of the bacterium's FtsZ protein, which is essential for cell division. FtsZ is not found in humans so targeting a unique protein like this should reduce the likelihood of side-effects in patients. Because of the novel mode of action of the new class of compounds, the levels of resistance in the bacterial population should be extremely low if a new drug was to emerge from this programme.
"The antibiotic that we are developing is far more selective than those currently in use, targeting only staphylococcal infections," says Dr Lloyd Czaplewski, Director of Research at Prolysis. "Other, broad-spectrum antibiotics tend to kill the patient's natural bacteria, leaving them open to secondary infection by other pathogenic bacteria, for example Clostridium difficile."
Given the urgent need for new antibacterials to tackle staphylococcal infections, Dr Czaplewski believes that the research, supported by this £3.48-million 33-month award, could result in a new medicine being fast-tracked into clinical evaluation by 2009.
The Wellcome Trust's Seeding Drug Discovery initiative aims to bridge the funding gap in early-stage drug discovery, assisting researchers to take forward projects in small molecule therapeutics that will be the springboard for further research and development by the biotech and pharmaceutical industry.
Contact
Craig Brierley
Media Officer
Wellcome Trust
T +44 (0)20 7611 7329
E
c.brierley@wellcome.ac.uk
Dr Lloyd Czaplewski
Director of Research
Prolysis Ltd
T +44 (0)1865 854700
E
lloyd.czaplewski@prolysis.com
Dr Steve Ruston
CEO
Prolysis Ltd
T +44 (0)1865 854700
E
steve.ruston@prolysis.com
Notes for editors
1. The Wellcome Trust is the largest independent charity in the UK and the second largest medical research charity in the world. It funds innovative biomedical research, in the UK and internationally, spending around £500 million each year to support the brightest scientists with the best ideas. The Wellcome Trust supports public debate about biomedical research and its impact on health and wellbeing.
2. Prolysis is an antibacterial drug discovery and development company with new classes of compounds in pre-clinical development. Novel antibacterial drugs are urgently needed to treat hospital-acquired and community-associated infections where existing therapies are failing due to antibiotic resistance. Prolysis uses a unique combination of antibacterial-focused drug-discovery technologies, including genetically engineered whole bacterial cell screens and structure-informed medicinal chemistry, to generate new antibacterials.
Prolysis was founded on the strength of the world-class bacterial cell biology of Professor Jeff Errington FRS. The company has transformed his insight into the process of bacterial cell division into efficient screening technologies and has deployed them to discover and optimise novel inhibitors of FtsZ.
3. Bacterial cell division is of considerable interest as a new antibacterial target. The process involves a large number of conserved proteins that are essential for the viability of bacteria. Furthermore, their activities are completely different from those in mammalian cells. Some of the most successful antibiotics, the beta-lactams and cephalosporins, target bacterial cell wall biosynthesis and cell division. Novel inhibitors of bacterial cell division are expected to be highly selective and free of mechanism-based toxicity to mammalian cells.
Bacterial cell division starts with the formation of a ring of FtsZ protein at the site of division. The FtsZ ring recruits key proteins to form a septasome that organises the synthesis of the new cell wall that forms the septum. Once septation is complete the daughter cells can separate. The process of FtsZ ring formation is dynamic, and by analogy with mammalian tubulin biology, compounds that can disrupt or stabilise the FtsZ rings may be found.
4. Prolysis' novel cell division inhibitor programme "CDI-936" emerged from an exploration of the structure-activity relationships (SAR) of inhibitors of FtsZ activity. A structure-informed medicinal chemistry optimisation programme led to the discovery of highly potent drug-like compounds that could produce a novel treatment for life-threatening infections. The compounds were effective against recent clinical Staphylococcal isolates including USA300 and PVL producing strains.
5. Prolysis will use the Seeding Drug Discovery Award to fund the completion of the drug discovery and development process to enable the evaluation of the compounds in human clinical trials.