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

抗微生物药物耐药性（AMR）每年在全球造成70万人死亡。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。考虑到这一点，到同一年，癌症的预计死亡率将达到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）呼吁寻找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。作为一个高技能团队的一部分，我们开发了两种新的抗菌化合物来治疗这些广泛耐药感染，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，它们对耐药细菌（包括世卫组织已宣布为新治疗的关键优先事项的细菌菌株）保持了这种高活性。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人类细胞系和活的蜡蛾幼虫无毒。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。这个项目将直接建立在我们的临床前数据的基础上，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。最终的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的讨论。在之前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，化合物的毒性水平，以及它们清除致病性大肠杆菌的能力。将研究大肠杆菌大腿感染。研究人员将密切监测小鼠，以记录化合物的任何影响。这些实验将降低该技术的风险，使其能够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 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.