Bacteria build essential survival molecules called polyprenyls that have no counterpart in human cells, yet drug hunters have largely ignored them because they are notoriously difficult to manufacture in the lab. This project develops new chemical methods to synthesise these bacterial membrane targets, then immobilises them on solid supports so that thousands of potential antibiotics can be tested against them quickly and systematically. The same approach will also produce chemically labelled targets to reveal exactly how existing antibiotics work and where resistance arises. If successful, the platform could unlock an entire class of overlooked antibiotic targets, giving researchers a practical way to screen natural products and synthetic compounds for candidates that kill resistant bacteria. Because the targets are unique to bacteria, any drugs found this way are less likely to harm human cells, potentially reducing side effects. This is fundamental synthetic chemistry with a clear translational goal: turning a synthetic bottleneck into a high-throughput discovery engine for the next generation of antibiotics.
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As the world recovers from the COVID-19 pandemic, the impact of infectious diseases has never been clearer. Antibiotics are vital to modern medicine, and they are prescribed to >80% of COVID-19 patients. Bacteria resistant to current antibiotics are emerging at an alarming rate. To prevent a future pandemic, we must find novel antibiotics. Bacteria produce many polyprenyl-containing biomolecules. These are unique to bacteria, essential for their survival, and not found in mammalian cells, making them and the enzymes that process them excellent antibiotic targets. However, this rich source of membrane targets is under exploited because they have traditionally been difficult to synthesize and there are insufficient high-throughput methods available to find new antibiotics that target them. In this proposal I outline a multidisciplinary approach, underpinned by synthetic organic chemistry, to address these challenges and identify new antibiotic candidates. My strategy is to develop: (1) novel methods to synthesize bacterial membrane-associated biomolecules; (2) an innovative platform to identify new antibiotics that bind to them; and (3) state-of-the-art strategies to investigate how these essential biomolecules interact with both enzymes and antibiotics. Immobilization of polyprenyl building blocks to solid supports, recently developed in my group, will allow for solid-phase antibiotic target synthesis. Immobilized targets will in turn be utilized in novel assays to identify new antibiotics from libraries of both natural products and synthetic small molecules. Furthermore, chemical modification of polyprenyls will allow production of labelled targets, enabling new studies aimed at understanding antibiotic mechanisms, and providing new avenues for antibiotic screening. These strategies will provide new opportunities for identifying antibiotic lead candidates through the development of breakthrough technologies for the fields of antibiotic discovery and glycobiology.
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