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Development of a new class of antibiotics to treat MRSA

Visit Wellcome Trust website

18 September 2008

A new class of drugs that kill MRSA in the lab has been discovered and could form the basis of new treatments to fight the infection, according to research published in Science* tomorrow (Friday).

Scientists from Prolysis, a British drug discovery and development company, and colleagues have created a class of drugs that selectively block the action of a protein called FtsZ, which bacteria need in order to grow. The drugs kill a range of bacteria, including methicillin-resistant and multi drug-resistant Staphylococcus aureus (MRSA).

The research was supported by the Wellcome Trust through its Seeding Drug Discovery programme, and by a LINK grant in applied genomics from the Biotechnology and Biological Sciences Research Council (BBSRC) and the former Department of Trade and Industry (DTI), now DIUS, as well as investors in Prolysis.

Lloyd Czaplewski, Director of Research at Prolysis, said: "By targeting this specific and essential bacterial protein, we have developed a class of drugs with a novel mechanism of action and the potential to treat MRSA and similar infections. Partnered with rapid diagnostics, it might also be used to prevent many of these infections in our hospitals and care homes.

"There’s still a lot of work to be done in terms of development and clinical studies, but we’re hopeful that in just a few years, we’ll see therapies based on this innovative approach in widespread use."

Ted Bianco, Director of Technology Transfer at the Wellcome Trust, said: "We’re delighted with the progress made by Prolysis and its partners. We have seen just two new classes of antibacterial drugs developed in the last 30 years. The progress being made by Prolysis in working towards an additional class of this much needed medicine is testament to the great science underpinning their R&D efforts."

ENDS

Notes to editors

* Haydon et al. (2008) "An Inhibitor of FtsZ with Potent and Selective Anti-Staphylococcus Activity" Science – doi: 10.1126/science.1159961

In 2007, there were 6,381 serious MRSA infections and an estimated 1,593 associated deaths in the UK.

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 optimize novel inhibitors of FtsZ. http://www.prolysis.com

Bacterial cell division and FtsZ: 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 stabilize the FtsZ rings may be found.

CDI-936: 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.

About the LINK Applied Genomics Programme

The LINK Applied Genomics Programme was launched in 2000 to exploit the increasing understanding of genomics for healthcare applications via the provision of support for collaborations between UK companies and academic research. The programme is led by the Biotechnology and Biological Sciences Research Council (BBSRC) along with two other sponsors: the former Department of Trade and Industry (DTI) – now the Department for Innovation, Universities and Skills (DIUS) – and the Medical Research Council (MRC).

About BBSRC

The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £420M in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, healthcare and pharmaceutical sectors. http://www.bbsrc.ac.uk

About the Wellcome Trust

The Wellcome Trust is the largest charity in the UK. It funds innovative biomedical research, in the UK and internationally, spending around £600 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. http://www.wellcome.ac.uk/

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