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

COVID-19大流行说明了未来应对新兴传染病的准备的必要性。虽然全世界有超过100万人死于COVID，但耐药细菌感染每年导致70万人死亡。新型冠状病毒肺炎（COVID-19）也加剧了抗生素耐药性危机，因为广谱抗生素的使用越来越多，同时也造成了大量住院患者，其中许多人接受了机械通气，他们面临多重耐药细菌感染的严重风险。近年来开发的抗生素大多是对现有类别的渐进式改进，共同承担耐药机制的责任。对于最难治疗的革兰氏阴性菌引起的感染，自20世纪70年代以来一直没有新的抗生素种类。我们的愿景是开发第一种新的抗生素用于治疗肠杆菌科，临床上最流行的革兰氏阴性菌病原体，50年来，并建立自行车作为一种新的治疗传染病的方式。在SBRI的资助下，我们已经应用了Bicycle公司专有的双环肽（_Bicycle_（r））技术，开发了抑制青霉素结合蛋白3（PBP 3）的强先导物，PBP 3是细菌细胞壁生物合成装置的一部分，也是β-内酰胺抗生素的关键靶点。我们的药物是一种全新的抗生素类，因此具有关键的区别：1\。我们的化合物不会被β-内酰胺酶灭活，而β-内酰胺酶会灭活最广泛使用的抗生素类β-内酰胺，并且不会显示出与现有抗生素类的交叉耐药性2\。我们的化合物使用一种新的机制进入细菌，并且预计不会由于外膜孔蛋白的损失或外排泵的上调而表现出摄取减少。我们已经开发出一种有效的PBP 3抑制剂，其具有有希望的抗菌效力和跨肠杆菌科的活性谱。我们对结合铅的晶体学研究显示了在广泛的结合表面上与酶活性位点的精致相互作用，并且我们通过与阳离子肽（“载体”）缀合改善了我们的“弹头”分子进入革兰氏阴性细菌。本申请的目标是开发准备进入I期临床试验的候选药物。关键目标是：通过提高“弹头”靶向亲和力和“载体”肽的效率来提高抗菌效力改善药代动力学以优化体内疗效研究耐药预后并确定可能的耐药机制进行正式的GLP安全性试验以确定启动临床试验的安全剂量，确定潜在的毒性机制并提供数据包以支持临床试验申请

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