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。发现新的抗菌药物线索是研发过程中的一个主要挑战。人们经常认为，制药公司的化合物集中在哺乳动物靶点上，缺乏具有成功抗生素典型结构特征的化合物。事实上，对这些化合物集合进行新抗生素筛选的效率很低，大多数成功的抗生素来自最初通过筛选环境中的微生物而发现的天然化合物。然而，这项技术本身的生产效率已经降低，因为从多年的筛选中已经发现了最有效、最常见的抗生素，必须付出越来越多的努力，以一种很大程度上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找到有用的新实体，但先前使用该类意味着它们往往容易产生耐药性（AMR）。我们的项目旨在通过应用一种专有的、超高通量的发现和优化技术来识别新型抗菌引线来解决这个问题。该技术能够识别具有天然产物抗菌药物特性的化合物，但使用的技术平台允许在短时间内从广泛的不同化学空间中识别多个目标的抑制剂。该技术平台最初由单克隆抗体的先驱Greg Winter爵士构想，并自2009年以来在Bicycle Therapeutics进一步发展。从那时起，已有90多个目标得到解决，成功率超过80%，导致两个正在进行的临床规划。因此，该平台在抗菌领域的应用已经得到了很好的验证和成熟。该项目将应用该平台发现青霉素结合蛋白（PBPs）抑制剂。这些是构建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，这是一种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点。然而，对这些抗生素类的耐药性是普遍存在的，针对这些目标的一类新的药物将具有巨大的治疗价值。我们将针对关键细菌病原体，金黄色葡萄球菌（包括MRSA），屎肠球菌和关键革兰氏阴性病原体，包括大肠埃希菌，铜绿假单胞菌和鲍曼不动杆菌。2017年，这些病原体都被世界卫生组织列为严重或高度威胁，并在英国医院造成重大问题

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