The Development and Study of Novel Lipopeptide Antibiotics and Enzyme Inhibitors

现代医学最重要的进步之一是抗生素的发现。不幸的是，细菌已经或开始对许多抗生素产生耐药性，包括所谓的最后防御抗生素：当所有其他更常见的抗生素都失效时，少数抗生素有效。因此，世界卫生组织已将抗菌素耐药性确定为人类健康的三大最重要问题之一。这项研究计划的主要内容是开发新的抗生素。我们使用一种叫做达托霉素（Dap）的环脂肽抗生素（cLPA）作为起点。Dap是一种重要的最后防御抗生素，用于治疗由革兰氏阳性菌引起的复杂感染。然而，对Dap的抵制开始出现。本提案的目标之一是开发与Dap相似但对Dap耐药细菌有活性的clpa。我们开发了一种化学合成Dap的方法。该方法将用于制备对dap耐药菌具有活性的clpa。这种方法也将用于开发广谱clpa，它对革兰氏阳性和革兰氏阴性细菌都有活性，可用于治疗细菌性肺炎。Dap通过破坏细菌膜来发挥作用，尽管它是如何破坏膜的还不完全清楚。因此，这项研究工作将辅以结构-功能研究，以确定Dap如何破坏细菌膜。这些研究结果将有助于设计具有更好抗抗性菌株活性的新型cLPAs。

One of the most important advances in modern medicine was the discovery of antibiotics. Unfortunately, bacteria have developed, or are beginning to develop, resistance to many antibiotics, including what are called last-defence antibiotics: a small number of antibiotics that are effective when all of the other more common antibiotics fail. Hence, the World Health Organization has identified antimicrobial resistance as one of the three most important problems for human health. The majority of this research proposal deals with the development of new antibiotics. We use as our starting point a cyclic lipopeptide antibiotic (cLPA) called daptomycin (Dap). Dap is an important, last-defence antibiotic used to treat complicated infections caused by Gram positive bacteria. However, resistance to Dap is beginning to appear. One of the goals of this proposal is to develop cLPAs that are similar to Dap yet are active against bacteria that are resistant to Dap. We have developed a method for chemically synthesizing Dap. This method will be employed to prepare cLPAs that are active against Dap-resistant bacteria. This approach will also be used to develop broad spectrum cLPAs that are active against Gram positive and Gram negative bacteria and can be used for treating bacterial pneumonia. Dap exerts its effect by disrupting bacterial membranes though exactly how it disrupt the membranes is not entirely clear. Consequently, this research effort will be complemented by structure-function studies to determine how Dap disrupts bacterial membranes. The results of these studies will facilitate the design of new cLPAs with improved activity against resistant strains. In addition to studies on antibiotics, this proposal also deals with the development of inhibitors of an enzyme called cytidine triphosphate synthase (CTPS), which is an anticancer, antiviral, and antiprotozoal target. CTPS inhibitors will be constructed using phosphorylation chemistry developed in our group. These inhibitors will be used to determine which residues are important for ligand binding and intermediate and transition state stabilization in the CTPS reaction. The results of these studies will provide information that will be crucial for developing drugs that target CTPS.