Development of a novel class antibiotic for therapy of carbapenem-resistant Enterobacteriaceae

点击翻译按钮获取中文摘要

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 antibiotics2\. 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 pumpsWe 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' peptideimprove pharmacokinetics to optimise _in vivo_ efficacyinvestigate resistance prognosis and identify possible mechanisms of resistanceperform 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