Tools and Reagents for Next Generation Inhibitor Discovery in Peptidoglycan biosynthesis

对现有抗生素的耐药性在多个层面上威胁着未来的医疗保健，并已被公认为一个全球性问题，其影响与气候变化一样重要。然而，尽管有明确的临床需求，但许多因素导致制药行业中抗菌药物的发现和开发稳步下降。在过去，该领域剩余的制药公司的抗菌研究和开发通常集中在尝试发现抗生素的新靶标或基于现有靶标的活性有限的新化合物。一般来说，这种方法取得的成功非常有限，再加上其他因素，意味着我们治疗细菌感染的药物数量越来越少，导致医疗保健危机。很明显，细菌擅长于选择单基因靶点的耐药性药物（即它们的蛋白质产物），并且过去成功的抗微生物化疗选择了其中存在多种必需活性的生物过程，例如在核糖体处的蛋白质合成，负责细胞中DNA超螺旋的蛋白质以及实现细菌细胞壁聚合物的形成和交联的机制。在这方面，称为肽聚糖的细菌细胞壁聚合物的生物合成是抗微生物剂的极好靶标，因为它提供了如上所述的多靶向的机会，不是在动物或人类中发现的结构，因此不良化学敏感性的机会较小，并且该过程发生在细胞外，允许药物分子更容易进入。虽然青霉素类药物过去已被用于利用这些优势，但它们的目标是相关细菌酶的交联活性。这些酶，称为青霉素结合蛋白，也负责肽聚糖聚合物的形成，以及在一个完全独立的反应，迄今为止一直在探索作为抗生素的目标。我们的建议旨在获得必要的知识，探索下一代抗生素这些酶。我们的建议将学术界和工业界的知识和进步联系起来，以互利的方式获得所需的关键信息。至关重要的是，我们需要产生一系列专门的化学探针来询问这些酶的工作机制，以确定与酶结合的这些探针的结构，以产生新的检测方法，从而发现未来的抗生素。

Antimicrobial resistance to existing antibiotics threatens future healthcare at multiple levels and has been acknowledged as a worldwide issue with an impact as important as climate change. However, a number of factors has led to a steady decline in the discovery and development of antimicrobials in the pharmaceutical industry despite the clear clinical need. The remaining pharmaceutical company antibacterial research and development in this area has focused generally in the past on either attempts to discover new targets for antibiotics or new compounds with limited activity profiles based on existing targets. Generally this approach has met with very limited success which combined with other factors, means we have a decreasing number of drugs to treat bacterial infection leading to a crisis in healthcare. It is clear that bacteria are adept at the selection of resistance to drugs for single gene targets (i.e. their protein products) and that the successful antimicrobial chemotherapy of the past, selects biological processes where there are multiple essential activities e.g. protein synthesis at the ribosome, the proteins which are responsible for DNA supercoiling in the cell and mechanisms by which formation and cross-linking of the bacterial cell wall polymer is achieved. The biosynthesis of the bacterial cell wall polymer called peptidoglycan is an excellent target for antimicrobials in this respect since it provides an opportunity for multi-targeting as described above, is not a structure found in animals or humans so there is less chance of adverse chemical sensitivity and the process occurs outside the cell allowing easier access for drug molecules. Whilst the penicillin group of drugs have been used to exploit these advantages in the past, they target the cross-linking activity of the bacterial enzymes concerned. These enzymes, called penicillin binding proteins, are also responsible for the formation of the peptidoglycan polymer as well in a completely separate reaction that has hitherto been under explored as a target for antibiotics.Our proposal seeks to gain the essential knowledge required to explore these enzymes for next generation antibiotics. Our proposal links the knowledge and advances in academia and industry in a mutually beneficial effort to get the key information required. Critically, we need to generate a series of specialist chemical probes to interrogate the mechanism by which these enzymes work, to determine the structures of these probes bound to the enzymes to generate new assays that will allow the discovery of future antibiotics.