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

随着世界从新冠肺炎疫情中恢复过来，传染病的影响从未像现在这样清楚。抗菌药对现代医学至关重要，80%的新冠肺炎患者都开了抗菌药。对当前抗生素产生抗药性的细菌正在以惊人的速度出现。为了防止未来的大流行，我们必须找到新的抗生素。细菌产生许多含有聚戊烯的生物分子。它们是细菌独有的，对它们的生存至关重要，在哺乳动物细胞中找不到，使它们和处理它们的酶成为极好的抗生素靶标。然而，这种丰富的膜靶标资源没有得到充分开发，因为它们传统上很难合成，而且没有足够的高通量方法来寻找针对它们的新抗生素。在这个提案中，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。我的战略是开发：(1)合成细菌膜相关生物分子的新方法；(2)识别与它们结合的新抗生素的创新平台；以及(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先进的策略。我的团队最近开发的固定化聚戊烯基团固相载体将允许固相合成抗生素靶标。固定化靶标将被用于新的分析，从天然产物和合成小分子的文库中鉴定新的抗生素。此外，聚戊烯的化学修饰将允许产生标记的靶标，使旨在了解抗生素机制的新研究成为可能，并为抗生素筛选提供新的途径。这些战略将通过开发抗生素发现和糖生物学领域的突破性技术，为确定抗生素主要候选者提供新的机会。

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.