Presenter: Dr Steven Polyak

University: The University of Adelaide

Time: 15:30-16:30, 26 May, 2011

Venue: A203, Institute of Microbiology, Chinese Academy of Sciences

Abstract:

Despite the availability of broad-spectrum antibiotics, microbial infection remains a significant health challenge worldwide. Bacterial strains resistant to existing antibiotics have now reached the stage where in Australia 200,000 hospital acquired infections result in ~12,000 serious blood stream infections per year. Staphylococcus aureus is the pathogenic agent responsible for more than half of these infections. Approximately 25% of these patients will die in hospital. Even more concerning is the estimation that 60% of methicillin-resistant S. aureus infections are now community-acquired. It is therefore imperative that we increase our efforts to develop new antibiotics with novel mechanisms of action to combat this inevitable march of resistance. Biotin protein ligase is an essential and multifunctional enzyme and, therefore, a potential drug target. The human homologue of this enzyme falls into a different structural class and we have shown that it is possible to design inhibitors that are selective for the S aureus enzyme over the human homologue. We have solved the X-ray crystal structure of S aureus BPL and characterised the step-wise binding of substrates. The adjacent biotin and ATP binding pockets evident in the 3D structure suggested that a fragment-based approach would be an ideal way to identifying novel inhibitor molecules. We have employed a combination of approaches to discover new enzymes inhibitors including X-ray crystallography, in silico fragment screening, binding analysis using surface plasmon resonance and enzyme catalysed fragment linkage or “templating”. These approaches have yielded a new class of BPL inhibitor with high potency, selectivity and, importantly, antibacterial activity.