NEW HOPE - NEW Approaches to Overcome the Problem of Antimicrobial Resistance

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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. Bacteriaresistant to current antibiotics are emerging at an alarming rate. To prevent a future pandemic, we must findnovel 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 themexcellent antibiotic targets. However, this rich source of membrane targets is under exploited because theyhave traditionally been difficult to synthesize and there are insufficient high-throughput methods available tofind new antibiotics that target them.In this proposal I outline a multidisciplinary approach, underpinned by synthetic organic chemistry, to addressthese challenges and identify new antibiotic candidates. My strategy is to develop: (1) novel methods tosynthesize bacterial membrane-associated biomolecules; (2) an innovative platform to identify newantibiotics that bind to them; and (3) state-of-the-art strategies to investigate how these essentialbiomolecules interact with both enzymes and antibiotics. Immobilization of polyprenyl building blocks tosolid 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 bothnatural products and synthetic small molecules. Furthermore, chemical modification of polyprenyls will allowproduction of labelled targets, enabling new studies aimed at understanding antibiotic mechanisms, andproviding new avenues for antibiotic screening. These strategies will provide new opportunities for identifyingantibiotic lead candidates through the development of breakthrough technologies for the fields of antibioticdiscovery and glycobiology.