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

随着世界从COVID-19大流行中复苏，传染病的影响从未如此清晰。抗生素对现代医学至关重要，80%的COVID-19患者使用抗生素。对现有抗生素具有耐药性的细菌正以惊人的速度出现。为了防止未来的大流行，我们必须找到新的抗生素。细菌产生许多含聚戊二烯的生物分子。这些是细菌所特有的，对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目标。然而，这种丰富的膜靶点来源尚未得到开发，因为它们传统上难以合成，并且没有足够的高通量方法来发现靶向它们的新抗生素。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，以解决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)一个创新的平台来识别与它们结合的新抗生素；(3)研究这些基本生物分子如何与酶和抗生素相互作用的最新策略。将聚戊烯基构建块固定在固体支架上，最近在我的小组中开发，将允许固相抗生素靶点合成。固定化靶标将被用于新的检测方法，从天然产物和合成小分子文库中鉴定新的抗生素。此外，聚戊烯基的化学修饰将允许生产标记靶点，使新的研究旨在了解抗生素的机制，并为抗生素筛选提供新的途径。这些策略将通过开发抗生素发现和糖生物学领域的突破性技术，为鉴定抗生素先导候选药物提供新的机会。

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.