Evolution of bicyclic peptides as penicillin binding protein inhibitors

作为青霉素结合蛋白抑制剂的双环肽的发展。发现新的抗菌药物的新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合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，筛选这些化合物集合的新抗生素的生产率很低，大多数成功的抗生素来源于最初通过从环境中筛选微生物发现的天然化合物。然而，这项技术本身的生产力已经降低，因为最有效的，最常见的抗生素已经从多年的筛选中发现，并且必须付出越来越多的努力来以一种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饰所主导。虽然可以通过这种方式发现有用的新实体，但该类的先前使用意味着它们倾向于产生耐药性（AMR）。我们的项目旨在通过应用专有的超高通量发现和优化技术来识别新型抗菌先导物来解决这个问题。该技术能够识别具有天然产物抗菌药物样特性的化合物，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靶标的抑制剂。该技术平台最初由单克隆抗体的先驱Greg Winter爵士构想，自2009年以来在Bicycle Therapeutics中得到了进一步发展。从那时起，已经解决了90多个目标，成功率超过80%，导致两个正在进行的临床项目。因此，该平台在抗菌领域的应用是经过充分验证和成熟的。该项目将应用该平台发现青霉素结合蛋白（PBP）的抑制剂。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中的任何结构，这是一种非常安全和有效的药物靶标，顾名思义，是重要的青霉素和头孢菌素抗生素的靶标。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药物将具有巨大的治疗价值。我们将针对主要细菌病原体的PBPs，包括金黄色葡萄球菌（包括MRSA）、屎肠球菌以及主要革兰氏阴性病原体，包括大肠杆菌、铜绿假单胞菌和鲍曼不动杆菌。这些病原体在2017年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

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