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败时，少数抗生素是有效的。因此，世界卫生组织已将抗生素耐药性确定为人类健康的三个最重要问题之一。该研究计划的大部分内容涉及新抗生素的开发。我们使用称为达托霉素（Dap）的环状脂肽抗生素（cLPA）作为我们的起点。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。该提案的目标之一是开发与Dap相似但对Dap耐药细菌具有活性的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抗性细菌具有活性的cLPA。该方法还将用于开发对革兰氏阳性和革兰氏阴性细菌具有活性并且可用于治疗细菌性肺炎的广谱cLPA。Dap通过破坏细菌细胞膜来发挥作用，但它究竟是如何破坏细胞膜的还不完全清楚。因此，这项研究工作将通过结构-功能研究来补充，以确定Dap如何破坏细菌膜。这些研究的结果将有助于设计对耐药菌株具有改善活性的新cLPA。*除了对抗生素的研究外，该提案还涉及一种称为三磷酸胞苷合酶（CTPS）的酶的抑制剂的开发，CTPS是抗癌，抗病毒和抗原虫的靶标。CTPS抑制剂将使用我们小组开发的磷酸化化学来构建。这些抑制剂将用于确定哪些残基对于CTPS反应中的配体结合以及中间体和过渡态稳定是重要的。这些研究的结果将为开发靶向CTPS的药物提供至关重要的信息。

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.