77556Advancing the development of a novel class of antibioticClosedCollaborative R&DInnovate UKWhilst 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.