Antimicrobial Resistance: Breakthrough Compound Discovery through Mechanistic Studies combined with Bicycle Technology and Target Validation

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Antimicrobial resistance (AMR) is a global strategic priority and sits within the UK Government's National Risk Register. In 2019 alone, there were an estimated 4.95 million deaths associated with bacterial AMR. Although global pharmaceutical research and development (R&D) spend continues to increase year on year, research into antimicrobial drug discovery is not currently an attractive commercial investment. This has had two major consequences: an ongoing decline of human capital for R&D in this field, and a decline over the longer term in availability of therapeutically effective antibiotics and other antimicrobial agents. Both training the next generation of leadership in the field and innovative approaches to tackle resistance with new therapeutics are urgently required, we aim to tackle both. BicycleTx has a portfolio of research areas that uses a unique technology platform to deliver high quality bi-cyclic peptides as potential therapeutics. This cross-sectional approach places the company in a rare position to commit some significant activity to search for effective antimicrobials alongside therapeutic areas that are typically more profitable, this is admirable.Warwick researchers have international reputation in their ability to develop new biochemical reagents, assays, structural and mechanistic insight into bacterial cell wall (peptidoglycan) biosynthesis. Recently co-located into a new building with state of the art facilities with additional appointments this team can study the whole biochemical pathway across scale, from models in silico, through atomic resolution to single molecules and single cell resolution. In the past year this opened up new tools, techniques and avenues of investigation. Our mostly commonly used antibiotics target peptidoglycan biosynthesis, many of these are natural products, such as penicillins and the wider family of beta-lactam antibiotics, to which resistance has developed, typically by the acquisition of enzymes that catalyse the destruction of the antibiotic or by mutation altering the target of the antibiotic. New molecules that sidestep such resistance mechanisms are really important for future developments.This academic industry partnership between researchers at the University of Warwick and BicycleTx will build upon an existing five year relationship to strengthen the Uk's life science research environment and address the great healthcare challenge which is AMR. The environment created by this partnership will provide training, enabling tools and technologies already in place from the existing relationship to progress through technology readiness levels TRL 2-4 while providing the freedom to explore new higher risk avenues of investigation that will require new targets and methods to be developed from basic research,TRL1, that may become the basis for future development, including the ability to better target Bicycles to penicillin binding proteins of WHO priority pathogens, including better permeation into difficult to kill gram negative bacteria, and access the bacterial cytoplasm and open up still further targets.We will deliver this in four work packages1: Extending the mechanistic understanding of existing Bicycle Penicillin Binding Protein inhibitors 2: Identification of new Bicycle inhibitors to additional therapeutic targets involved in bacterial cell wall production & maintaining bacterial viability. Adding these into WP1 3: Computational modelling to design next generation molecules to enable Bicycle delivery into the periplasm and cytoplasm of bacteria and evasion of the potential for mutational resistance 4: Combining outputs from WP2 and WP3 to generate novel prototypical antimicrobial agents.Additionally our existing partnership and wider relationships across the AMR sector will facilitate a streamlined working relationship and expectations of delivery, alongside a unique training environment for the next generation of research leaders.