To transfer knowledge and techniques required to develop novel antibiotics. The KTP will focus on the development of methods to screen for new prototype antibiotics and apply the screens in the laboratory. The KTP brings together expertise in bacterial biology in the KB and expertise in drug discovery from industry.

The COVID-19 pandemic illustrates the need for future preparedness to tackle emerging infectious diseases. Whilst \>1 million people worldwide have died from COVID, antibiotic-resistant bacterial infections kill 700,000 people every year. COVID-19 has also exacerbated the AMR crisis by increasing use of broad-spectrum antibiotics, and also creating a reservoir of hospitalised patients, many ventilated, who are at severe risk from multi-drug resistant bacterial infections. Antibiotics which have been developed in recent years are mostly incremental improvements on existing classes, sharing common liabilities to resistance mechanisms. For the most difficult to treat infections caused by Gram-negative bacteria, there has been no new class of antibiotic introduced since the 1970s. Our vision is to develop the first new class antibiotic for therapy of Enterobacteriaceae, the most clinically-prevalent class of Gram-negative bacterial pathogens, for 50 years and to establish Bicycles as a new therapeutic modality for infectious diseases. Under SBRI funding, we have applied Bicycle's proprietary bicyclic peptide (_Bicycle_(r)) technology, to develop strong leads which inhibit penicillin binding protein 3 (PBP3), part of the bacterial cell wall biosynthetic apparatus and a key target of the beta-lactam antibiotics., Our agents are of a totally new antibiotic class, and so have key differentiators: 1\. Our compounds are not inactivated by beta-lactamase enzymes which inactivate the most widely used antibiotic class, the beta-lactams, and do not show cross-resistance with existing classes of antibiotics 2\. Our compounds enter bacteria using a novel mechanism and are not expected to exhibit reduced uptake due to a loss of outer membrane porins or upregulation of efflux pumps We have already developed a potent inhibitor of PBP3 which has promising antibacterial potency and spectrum of activity across Enterobacteriaceae. Our crystallographic work on the bound lead shows exquisite interactions with the enzyme active site across a broad binding surface and we have improved entry of our 'warhead' molecule into Gram-negative bacteria by conjugation to a cationic peptide ('vector'). . The goal of this application is to develop a drug candidate ready to enter a phase I clinical trial. Key objectives are: increase antibacterial potency by improving the 'warhead' target affinity and the efficiency of the 'vector' peptide improve pharmacokinetics to optimise _in vivo_ efficacy investigate resistance prognosis and identify possible mechanisms of resistance perform formal GLP safety testing to identify a safe dose to initiate clinical testing, identify potential toxic mechanisms and provide a data package to support a clinical trial application

Whilst the COVID-19 pandemic has caused the death of \>500,000 people worldwide this year, antibiotic-resistant bacterial infections are killing 700,000 people every year. The worldwide effort to develop new antibiotics has suffered severe dislocation during the COVID pandemic. Worse still COVID has increased use of broad-spectrum antibiotics due to the threat of bacterial co-infections thus fuelling the AMR crisis, as well as creating a large reservoir of hospitalised patients, many ventilated, who are at genuine risk of contracting multi-drug resistant bacterial infections. Whilst new antibiotics have been developed they are mostly incremental improvements on existing classes, sharing ultimately the same liability to resistance mechanisms. For Gram-negative bacterial infections, one of the most difficult to treat and prevalent in our hospitals, there has been no new class of antibiotic introduced since the 1970s. This is the problem we seek to address. With support from the SBRI programme, we have used Bicycle's proprietary bicyclic peptide (_Bicycle_(r))technology, to develop strong leads against penicillin binding protein 3 (PBP3), part of the bacterial cell wall biosynthetic apparatus and a key target of the beta-lactam antibiotics. However, our agents, which are of a totally new chemical class, will not suffer the same resistance liabilities, namely: 1\. Inactivation by beta-lactamase enzymes -- our agents have no such liability 2\. Reduced uptake into bacteria due to loss of outer membrane porins and efflux -- our agents have a totally different mechanism of entering bacteria We have already made substantial progress. We have developed a potent inhibitor of PBP3 in Enterobacteriaceae and, despite the pandemic, determined the crystal structure of the bound lead which shows exquisite interactions with the enzyme active site across a broad binding surface.. Our lead has promising antibacterial potency and species spectrum of activity even against the most difficult to treat bacteria. To raise further funding, we need to show _in vivo_ efficacy which requires compound stabilisation to confer acceptable pharmacokinetics. Bicycle has a well-developed tool-box of previously successful approaches to apply to this goal. We propose a short, focussed project to secure this key progression step. Much of the momentum lost due to COVID can be recovered if we can address this step quickly so we can be well-placed to apply for upcoming national and international funding opportunities. Bicycle's business is now COVID robust. Infrastructure and procedural modifications allow work to be carried out efficiently in our own laboratories. Furthermore, the CROs, to whom we propose to outsource key _in vivo_ experiments, have continued to operate through the pandemic. The pandemic has demonstrated the potential global economic impact arising from the failure to prepare for public health issues. Earlier this month a consortium of 23 top pharmaceutical companies established the $1bn AMR Action fund to support clinical development of new antibiotics. A pilot scheme has been recently established in the UK to provide much needed market incentives for new antibiotics. The field is poised for a 'COVID-induced' stimulus. This funding is needed to position Bicycle to be part of the much-needed response to AMR.

Bicycles are a new class of drug that can rapidly be identified using our unique platform technology and have utility if they can be developed as novel anti-virals for use in tackling the current and/or future covid pandemics. They also have potential as novel anti-inflammatory therapies tailored to the requirements of later stage Covid-19 disease sufferers that go on to develop severe inflammatory conditions in the hospital setting. In this application we propose a multi-target strategy to identify novel therapies to treat the ongoing, and potentially future, pandemics.

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

"Resistance to antibiotics is a major public health threat that could have huge impact on medicine and indeed our way of life. Reports have suggested that without substantial interventions, 100 million people could die from infection from antibiotic-resistant bacteria by 2050\. The issue is not just deaths from untreatable infection but the inability to carry out other medical procedures such as elective surgery, transplantation and cancer chemotherapy without effective antibiotics. It has been estimated that the economic cost could be $100 trillion or 2.5% of World GDP. Development of new antibiotics has stalled partly for economic reasons in that antibiotic development in recent years has not provided a sufficient return on investment, but partly also for technical reasons in that it has proved extremely difficult to develop new antibiotics. Some success has been achieved in developing new members of existing classes of antibiotics, but only three new classes of antibiotics have been introduced in the last 40 years. Bicycle Therapeutics has developed a game-changing new lead discovery technology which has proven extremely productive in the oncology field and is also being exploited in collaboration with major pharmaceutical companies in ophthalmology, respiratory, cardiovascular and metabolic diseases. This platform has tremendous potential for application to development of new antibiotics. Development of new antibiotics has been extremely difficult because the compound collections of pharmaceutical companies are not well-suited to antibacterial applications. Furthermore, the ideal targets for development of new antibacterials are complex and recalcitrant to traditional drug discovery approaches. Only natural molecules optimised over millions of years by evolution have tended to be successful, but new ones are proving harder and harder to find. The Bicycle technology employs bacteriophage (viruses of bacteria) to generate and present drug-like molecules in huge numbers, many orders of magnitude greater than could be achieved by synthetic chemistry, and test them for target binding while still attached to the bacteriophage. The population can therefore be enriched for promising leads through multiple evolutionary cycles. The power of the approach is similar to natural selection in evolution, but conducted over months rather than millennia. Our goal is to generate proof-of-principle data for this approach against antibacterial targets and, if successful, to establish a spin-off company to utilize the technology against a broad range of antibacterial targets. We believe that this innovative technology, new to the antibacterial field but proven elsewhere, could have a major impact on the antimicrobial resistance problem."

Awaiting Public Project Summary

Awaiting Public Project Summary