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

新希望 - 克服抗菌素耐药性问题的新方法

• 批准号: EP/Y027728/1
• 负责人: Stephen Cochrane
• 金额: $ 161.85万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FY027728%2F1
• 关键词: NEW; HOPE; Approaches; Overcome; Problem

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.

随着世界从 COVID-19 大流行中恢复过来，传染病的影响从未如此明显。抗生素对现代医学至关重要，超过 80% 的 COVID-19 患者需要使用抗生素。对现有抗生素产生耐药性的细菌正以惊人的速度出现。为了预防未来的大流行，我们必须找到新型抗生素。细菌产生许多含聚异戊二烯的生物分子。这些是细菌所独有的，对于它们的生存至关重要，并且在哺乳动物细胞中没有发现，这使得它们和处理它们的酶成为极好的抗生素靶点。然而，这种丰富的膜靶点来源尚未得到充分利用，因为它们传统上难以合成，并且没有足够的高通量方法来寻找针对它们的新抗生素。在本提案中，我概述了一种以合成有机化学为基础的多学科方法，以应对这些挑战并确定新的候选抗生素。我的策略是开发：（1）合成细菌膜相关生物分子的新方法； (2) 一个创新平台，用于识别与其结合的新抗生素； (3) 研究这些重要生物分子如何与酶和抗生素相互作用的最先进策略。我的小组最近开发了将聚异戊二烯结构单元固定在固体支持物上，这将允许固相抗生素靶标合成。固定化靶标将反过来用于新的测定中，以从天然产物和合成小分子库中识别新的抗生素。此外，聚异戊二烯的化学修饰将允许生产标记靶标，从而实现旨在了解抗生素机制的新研究，并为抗生素筛选提供新途径。这些策略将为通过开发抗生素发现和糖生物学领域的突破性技术来识别先导抗生素提供新的机会。