Two novel ruthenium antimicrobial compounds to treat Gram-negative, pathogenic, multi-drug resistant infections.

抗生素耐药性（AMR）每年在全球造成70万例死亡。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，到同一年，癌症的预测死亡率将达到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。作为一个高技能团队的一部分，我们已经开发出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。这些化合物显示出与临床抗生素相当的活性，但关键是它们保留了对耐药细菌的高活性，包括细菌菌株。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人类细胞系和活的蜡螟幼虫无毒。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，加速技术的开发，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。最终活性和毒性研究将在细胞系中进行（在试管/培养皿中），这些研究的数据将用于促进共同开发讨论。为了建立在先前的活体模型数据的基础上，将在小鼠模型中研究药物的吸附、分布、代谢和排泄特性。此外，该化合物的毒性水平，以及其清除致病菌的能力。大肠杆菌大腿感染进行研究。在研究中将密切监测小鼠，以记录化合物的任何影响。这些实验将降低该技术的风险，使其发展到中等动物临床前模型。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 700,000 annual fatalities. Failure to address this issue by 2050 could result in 10 million deaths per year, costing the global economy £66 trillion. To put this into context, the predicted death rate for cancer will be 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, we 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 they 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 and in living wax moth larvae. In addition, both compounds cleared a fatal infection from the larvae using a single dose.This project will directly build upon our preclinical data, accelerating the technology's development, reducing our time to market. This will increase the probability of the compounds successfully reaching the clinic. Final activity and toxicity studies will be carried out in cell lines (in a test tube/culture dish) and data from these studies will be used to facilitate co-development discussions. To build upon the previous living model data, the adsorption, distribution, metabolism and excretion properties of the drugs will be studied in a mouse model. In addition, the compounds toxicity levels, and their ability to clear a pathogenic _E. coli_ thigh infection will be studied. The mice will be closely monitored in the studies to record any effects of the compounds. These experiments will de-risk the technology, allowing its progression onto a medium animal pre-clinical model.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.