Photo supplied by: University of Adelaide
Inhibitors of biotin protein ligase: A new class of antibiotic targeting Staphylococcus aureus
University of Adelaide | 2011 | Project Grant | $605,963
Team members: Dr Steven Polyak, Prof Grant Booker, Emeritus Professor John Wallace, Professor Matthew Wilce, Professor Robert Milne, Professor John Turnidge, Dr David Ogunniyi, Dr William Tieu, Dr Beatrix Blanco-Rodriguez, Dr Tatiana Soares da Costa and Professor Daniel Sejer Pedersen.
The World Health Organisation (WHO) has described antimicrobial resistance as one of the key global health issues facing our generation.1 The lack of new antibiotics coupled with their over-prescription has led to bacteria becoming increasingly resistant—rendering existing antibiotics less effective and placing patients at greater risk of dying from common infections. Without antibiotics, complex surgical procedures such as organ transplants would also not be possible.
‘Nineteen per cent of serious blood infections in Australia are resistant to antibiotics—a rate higher than in France, Germany and the United Kingdom.2’
With only two new antibiotic classes being discovered and developed in the last 50 years, Professor Andrew Abell and his team at the University of Adelaide are going back to the fundamentals of chemical science in an attempt to develop a new class of antibiotics.
Motivated by a desire to understand the molecular basis of key biological processes, Professor Abell saw an opportunity to use small molecules that selectively bind to bacterial proteins, as a potential mechanism for limiting bacterial survival.
‘This project successfully employed chemistry and biochemistry to understand the complex nature of biotin—vitamin B7—both in the test tube and inside the bacteria,’ Professor Abell said.
‘We are using this knowledge to discover a new antibacterial by inhibiting a key protein—known as biotin protein ligase (BPL)—to disrupt how bacteria use this important micronutrient, rendering the bacteria unable to survive.’
‘We are particularly excited about one compound—BPL199—showing potent activity against multiple strains of Golden Staph, including drug resistant strains like MRSA (Methicillin-resistant Staphylococcus aureus),’ Professor Abell explained.
Professor Abell and his team’s approach to antibacterial discovery involves ‘smart medicinal chemistry’ to design, make and then test new compounds that have the potential to be developed into antibiotics. It brought together a large group of scientists, working in a highly collaborative fashion.
‘There is a desperate need to replenish the antibiotic pipeline with new products to combat drug resistance. We are developing novel classes of antibiotics with potential to treat infections caused by pathogenic bacteria, including Golden Staph.’
‘This strategy requires the contribution of medicinal chemists, biochemists, structural biologists, microbiologists and pharmacologists,’ Professor Abell said.
‘Medicinal chemistry can then draw upon this fundamental knowledge to best exploit our approach. This requires a truly multidisciplinary approach to science with a strong awareness of commercial opportunities and demands.’
‘Drug discovery projects often fail as researchers do not understand enough about the fundamentals of the drug targets they work on,’ he said.
Professor Abell and his team are now working towards improving the pharmacological properties of BPL199. This involves designing new chemical products that will improve the activity of the compound in animal models of disease. The team will also begin to expand their research and findings to new areas of human health and disease to improve the health of all Australians.
1 Cruickshank M & Ferguson J, 2008. Reducing harm to patients from health care associated infection: the role of surveillance. Sydney: Australian Commission on Safety and Quality in Health Care (ACSQHC)
2 Australian Government, 2014 Responding to the threat of antimicrobial resistance: Australia’s First National Antimicrobial Resistance Strategy 2015-2019