Evolution of bicyclic peptides as penicillin binding protein inhibitors

双环肽作为青霉素结合蛋白抑制剂的进化

• 批准号: 971626
• 金额: $ 63.25万
• 依托单位: BICYCLETX LIMITED
• 依托单位国家: 英国
• 项目类别: Small Business Research Initiative
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=971626
• 关键词: Evolution; bicyclic; peptides; penicillin; binding

Evolution of bicyclic peptides as penicillin binding protein inhibitors .Discovery of novel leads for new antibacterial drugs is a major challenge in the R&D process. It is often argued that the compound collections of pharmaceutical companies are focussed around mammalian targets and lack compounds with structural features typical of successful antibiotics. Indeed screening of these compound collections for new antibiotics has been poorly productive and most successful antibiotics derive from natural compounds originally discovered by screening microorganisms from the environment. This technology, however, has itself become less productive as the most potent, commonly-produced antibiotics have been already discovered from many years of screening, and more and more effort must be applied to find new entities in a largely serendipitous fashion. This has led to the antibiotic R&D field becoming dominated by the further modification of existing antibiotic classes. Although useful new entities can be found in this way, the prior use of the class means that they tend to be prone to resistance development (AMR). Our project aims to address this problem by applying a proprietary, ultra high-throughput discovery and optimisation technology to the identification of novel antibacterial leads. The technology has the capability to identify compounds with the antibacterial drug-like properties of natural products, but using a technology platform which allows inhibitors of multiple targets to be identified in a short period of time from vast diverse chemical space. The technology platform was originally conceived by Sir Greg Winter, a pioneer of monoclonal antibodies, and has been further developed in Bicycle Therapeutics since 2009. Since that time more than 90 targets have been addressed with an 80%+ success rate leading to two ongoing clinical programmes. The platform is therefore well-validated and ripe for application in the antibacterial field. This project will apply the platform to the discovery of inhibitors of penicillin binding proteins (PBPs). These are the key catalysts which build the bacterial cell wall. As the bacterial cell wall is unlike any structures in mammals this is an extremely safe and effective drug target and, as the name suggests, the target of the important penicillin and cephalosporin antibiotics. However, resistance to these antibiotic classes is widespread and a new class of agents addressing these targets would be of huge therapeutic value. We will target the PBPs of key bacterial pathogens, Staphylococcus aureus (including MRSA), Enterococcus faecium and also key Gram-negative pathogens including Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii. These pathogens were all classified by the WHO in 2017 as Critical or High threats and cause significant problems in UK hospitals

双环肽作为青霉素结合蛋白抑制剂的研究进展。寻找新的抗菌药物的新先导是研发过程中的主要挑战。人们经常认为，制药公司的化合物收藏集中在哺乳动物的靶标上，缺乏具有成功抗生素典型结构特征的化合物。事实上，对这些化合物收集的新抗生素的筛选一直成效不佳，大多数成功的抗生素来自最初通过从环境中筛选微生物而发现的天然化合物。然而，这项技术本身已经变得不那么有成效了，因为在多年的筛选中已经发现了最有效、最常见的抗生素，而且必须付出越来越多的努力，以基本上是偶然的方式发现新的实体。这导致抗生素研发领域被现有抗生素类别的进一步修改所主导。虽然可以通过这种方式发现有用的新实体，但类的先前使用意味着它们往往容易出现抗药性发展(AMR)。我们的项目旨在通过应用专利的超高通量发现和优化技术来识别新的抗菌线索来解决这个问题。这项技术有能力识别具有天然产品抗菌药物性质的化合物，但使用了一种技术平台，允许在短时间内从巨大的不同化学空间中识别出多个目标的抑制剂。该技术平台最初由单抗先驱格雷格·温特爵士构思，自2009年以来在自行车治疗公司得到进一步开发。自那时以来，已有90多个目标被解决，成功率超过80%，导致了两个正在进行的临床计划。因此，该平台得到了很好的验证，并且在抗菌领域的应用已经成熟。该项目将把该平台应用于青霉素结合蛋白(PBPs)抑制剂的发现。这些都是构成细菌细胞壁的关键催化剂。由于细菌细胞壁不同于哺乳动物的任何结构，这是一个极其安全有效的药物靶点，顾名思义，它也是重要的青霉素和头孢菌素类抗生素的靶标。然而，对这些抗生素类别的耐药性是普遍存在的，针对这些靶点的新一类药物将具有巨大的治疗价值。我们将针对主要细菌病原体金黄色葡萄球菌(包括耐甲氧西林金黄色葡萄球菌)、粪肠球菌以及主要革兰氏阴性病原体包括大肠埃希菌、铜绿假单胞菌和鲍曼不动杆菌的PBPs。这些病原体在2017年都被世界卫生组织归类为严重或高度威胁，并在英国医院造成重大问题