Evolution of bicyclic peptides as penicillin binding protein inhibitors

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