Mechanism of Action and Lead Optimisation of a Novel Antimicrobial Class

抗菌素耐药性（AMR）每年在全球造成120万例死亡。如果到2050年不能解决这个问题，每年可能导致1000万人死亡，使全球经济损失66万亿英镑。在此背景下，同年癌症的预测死亡率为820万。由于目前的抗生素不起作用，轻微的伤害，如膝盖上的擦伤，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）呼吁采用新的方法来治疗抗生素耐药性感染。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。作为一支技术精湛的团队的一员，MetalloBio开发了两种新型抗菌化合物，用于治疗这些广泛耐药的感染，而其他抗生素则无法治疗这些感染。这些化合物表现出与临床抗生素相当的活性，但关键是保留了对耐药细菌的高活性，包括WHO宣布为新治疗关键优先的细菌菌株。复合物本身具有模块化合成。就像乐高一样，我们可以交换现有线索的“积木”，制造出一系列潜在的药物。已发现这两种化合物对蜡螟幼虫和啮齿动物中的人类细胞系无毒。此外，这两种化合物都可以通过单次给药清除幼虫的致命感染。该项目将直接建立在我们的临床前数据基础上，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到达临床的可能性。将研究两种化合物的全部作用机制，并确定两种化合物对铜绿假单胞菌的疗效模型。这些实验将降低该技术的风险，使其能够在中型动物模型上发展。我们的化合物探索了抗菌化学的新领域，它们的结构与临床上的任何抗生素都完全不同。这将减少出现耐药性的可能性，提高治疗感染的能力，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.