Mechanism of Action and Lead Optimisation of a Novel Antimicrobial Class

抗菌素耐药性(AMR)每年导致全球120万人死亡。如果不能在2050年之前解决这个问题，可能会导致每年1000万人死亡，全球经济损失66万亿GB。与此相关的是，到同一年，癌症的预计死亡率为820万。由于目前的抗生素无效，轻微的伤害，如膝盖的擦伤，可能很快就会成为致命的。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。我们的团队正在直接响应这一呼吁，与英国政府到2040年控制和遏制AMR的20年愿景保持一致。作为一个高技能团队的一部分，MetalloBio开发了两种新型抗菌化合物，用于治疗这些其他抗生素无效的广泛耐药感染。这些化合物显示出与临床抗生素类似的活性，但至关重要的是，它对耐药细菌保持了这种高活性，包括世界卫生组织宣布为新治疗关键优先事项的细菌菌株。这些络合物本身有一个模数合成。就像乐高一样，我们可以交换目前线索的“积木”，以制造一整套潜在的药物。这两种化合物对蜡蛾幼虫和啮齿动物的人体细胞系都被发现是无毒的。此外，这两种化合物都只用一剂就清除了幼虫的致命感染。这个项目将直接建立在我们的临床前数据的基础上，包括已经确定的毒理学和小鼠的药代动力学特征，加快技术的开发，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。将研究这两种化合物的全部作用机制，并确定这两种化合物对铜绿假单胞菌药效模型的药效。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。我们的化合物探索了抗菌化学的一个新领域，它们的结构与临床上的任何抗生素都是完全不同的。这将减少出现耐药性的可能性，提高治疗感染的能力和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.