Mechanism of Action and Lead Optimisation of a Novel Antimicrobial Class

抗菌素耐药性（AMR）在全球每年造成120万人死亡。如果到2050年不能解决这一问题，每年将导致1000万人死亡，全球经济损失66万亿英镑。在此背景下，到同一年，癌症的预计死亡率为820万。由于目前的抗生素效果不理想，轻微的伤害，比如膝盖上的划伤，可能很快就会致命。为了应对这一紧急情况，世界卫生组织（WHO）呼吁采用新方法治疗抗生素耐药感染。我们的团队直接响应这一呼吁，符合英国政府到2040年控制和遏制AMR的20年愿景。作为一个高技能团队的一部分，MetalloBio已经开发出两种新的抗菌化合物来治疗这些广泛耐药的感染，而其他抗生素都不起作用。这些化合物表现出与临床抗生素相当的活性，但至关重要的是，它们保留了对耐药细菌的高活性，包括世卫组织宣布为新疗法关键优先事项的细菌菌株。配合物本身具有模合成。就像乐高积木一样，我们可以交换现有线索的“积木”，制造出一系列潜在的药物。这两种化合物已被发现对蜡蛾幼虫和啮齿动物的人类细胞系无毒。此外，这两种化合物使用一次剂量就能清除幼虫体内的致命感染。该项目将直接建立在我们的临床前数据的基础上，包括已经确定的小鼠毒理学和药代动力学特征，加速技术的发展，缩短我们的上市时间。这将增加化合物成功进入临床的可能性。这两种化合物的作用机制将被研究，并确定两种化合物对铜绿假单胞菌的功效模型。这些实验将降低这项技术的风险，使其能够发展到中等动物模型上。我们的化合物探索了抗菌化学的新领域，它们的结构与临床中的任何抗生素完全不同。这将减少出现耐药性的可能性，提高治疗感染的能力，并改善患者的生活质量。

Antimicrobial resistance, AMR, is globally responsible for 1.2 million annual fatalities. Failure to address the issue by 2050 could result in 10 million deaths per year, costing the global economy £66 trillion. To put this in to context, the predicted death rate for cancer is 8.2 million by the same year. As current antibiotics fail minor injuries, like a scratch on the knee, could soon become fatal. To address this emergency, the World Health Organisation, WHO, has called for novel methods to treat antibiotic resistant infections. Our team are directly answering this call, in line with the UK Government's 20-year vision to control and contain AMR by 2040\. As part of a highly skilled team, MetalloBio have developed two novel antimicrobial compounds to treat these extensively-drug resistant infections where other antibiotics are failing.The compounds exhibit comparable activities to clinical antibiotics but, crucially retain this high activity against drug-resistant bacteria, including bacterial strains the WHO has declared as critical priorities for new treatments. The complexes themselves have a modular synthesis. Like Lego, we can exchange the "building blocks" of our current leads to make a whole series of potential drugs. Both compounds have been found to be non-toxic to human cell lines in wax moth larvae and rodents. In addition, both compounds cleared a fatal infection from the larvae using a single dose.This project will directly build upon our preclinical data, including already determined toxicology and pharmacokinetic profiles in mice, accelerating the technology's development, reducing our time to market. This will increase the probability of the compounds successfully reaching the clinic. The full mechanism of action of both compounds will be studied and the efficacy of both compounds against a P. aeruginosa efficacy model determined. These experiments will de-risk the technology, allowing its progression onto medium animal models.Our compounds explore a new area of antimicrobial chemistry, their structures are radically different to any antibiotics in the clinic. This will reduce the likelihood of resistance emerging, increasing the capability to treat infections and improve patient quality of life.