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

新冠肺炎大流行表明，未来需要做好准备，以应对新出现的传染病。虽然全世界有100万人死于冠状病毒感染，但耐药细菌感染每年导致70万人死亡。新冠肺炎还通过增加广谱抗生素的使用加剧了急性呼吸道耐药危机，还造成了住院患者的储备库，其中许多人已经呼吸机，他们面临着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，分担耐药机制的共同责任。对于最难治疗的革兰氏阴性菌引起的感染，自20世纪70年代以来就没有推出新的抗生素类别。我们的愿景是开发50年来第一个用于治疗肠杆菌科的新类别抗生素，肠杆菌科是临床上最常见的革兰氏阴性细菌病原体，并建立自行车作为感染性疾病的新治疗方式。在SBRI的资助下，我们应用Bcycle公司专有的双环肽(_Bcycle_(R))技术，开发出能够抑制青霉素结合蛋白3(PBP3)的强先导化合物，这是细菌细胞壁生物合成装置的一部分，也是β-内酰胺类抗生素的关键靶点。我们的试剂属于一种全新的抗生素类别，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，这种酶会使最广泛使用的抗生素类--β-内酰胺类失活，并且与现有的抗生素类不表现出交叉耐药性。我们的化合物使用一种新的机制进入细菌，预计不会由于外膜孔蛋白的损失或外排泵的上调而减少摄取。我们已经开发出一种有效的PBP3抑制剂，它具有良好的抗菌效力和在肠杆菌科的活性谱。我们对结合铅的结晶学研究显示，我们与酶活性部位在广泛的结合表面上发生了精细的相互作用，我们通过与阳离子多肽(“载体”)的结合，改善了我们的“弹头”分子进入革兰氏阴性细菌的能力。该应用程序的目标是开发一种准备进入I期临床试验的候选药物。主要目标是：通过改善弹头靶标亲和力和载体多肽的效率来提高抗菌效力改善药代动力学以优化体内效率研究耐药预后并确定可能的耐药机制执行正式的GLP安全测试以确定安全剂量以启动临床试验，确定潜在的毒性机制并提供数据包以支持临床试验应用

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