Antimicrobial Resistance: Breakthrough Compound Discovery through Mechanistic Studies combined with Bicycle Technology and Target Validation
Lead Research Organisation:
University of Warwick
Department Name: School of Life Sciences
Abstract
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 packages
1: 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.
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 packages
1: 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.
Technical Summary
At its core, this Prosperity Partnership will link the technical expertise of Warwick academics with the drug discovery capabilities of BicycleTx. BicycleTx's ambition is a hugely expanded antimicrobial compound portfolio, however experience from the high-throughput antimicrobial screening campaigns of large pharma companies in recent decades has been that without thorough and specialised target knowledge, programmes fail. Whilst the experts at BicycleTx can screen targets and develop hits to leads, partnering is needed to incorporate the specific microbiological, computational, and biochemical knowledge.
Our work to date has identified three key fundamental biology questions which require further understanding to enable progress. These questions motivate and correspond to WPs1-4: aiming to deliver
Kinetic values for the binding of Bicycles to PBP3, current and novel assays, in the presence of the natural substrate, with comparison to beta-lactam controls.
Molecular modelling and simulations of the binding of known, as well as alternative, Bicycles to PBP3.
Molecular simulations of the interactions and relative binding free energy calculations to evaluate the protein-ligand complexes.
Bicycle series (discovered by phage binding) to at least 2 new periplasmic targets.
Assays, protein and crystallography developed and in place for Bicycle characterisation and optimisation (WP4).
A molecular understanding of Bicycle interactions with biological membranes, including both inner and outer membranes of Gram-negative bacteria. The studies will commence with E. coli and expand to other pathogenic bacteria, A. baumannii and P. aeruginosa.
A set of molecular rules for Bicycle permeation across membranes, with the potential to also optimise the central conjugate ring to enhance membrane solubility, whilst retaining target binding.
At least one series of validated Bicycles against a novel bacterial target and CARB-X data package.
Our work to date has identified three key fundamental biology questions which require further understanding to enable progress. These questions motivate and correspond to WPs1-4: aiming to deliver
Kinetic values for the binding of Bicycles to PBP3, current and novel assays, in the presence of the natural substrate, with comparison to beta-lactam controls.
Molecular modelling and simulations of the binding of known, as well as alternative, Bicycles to PBP3.
Molecular simulations of the interactions and relative binding free energy calculations to evaluate the protein-ligand complexes.
Bicycle series (discovered by phage binding) to at least 2 new periplasmic targets.
Assays, protein and crystallography developed and in place for Bicycle characterisation and optimisation (WP4).
A molecular understanding of Bicycle interactions with biological membranes, including both inner and outer membranes of Gram-negative bacteria. The studies will commence with E. coli and expand to other pathogenic bacteria, A. baumannii and P. aeruginosa.
A set of molecular rules for Bicycle permeation across membranes, with the potential to also optimise the central conjugate ring to enhance membrane solubility, whilst retaining target binding.
At least one series of validated Bicycles against a novel bacterial target and CARB-X data package.
