Exploring novel binding pockets in DNA gyrase and DNA topoisomerase IV to address antibiotic resistance

抗微生物药物耐药性（AMR）可能是当前对人类健康的最大威胁。最近的估计（奥尼尔报告，2016年）表明，到2050年，每年可能有1000万人死于抗生素耐药性。此外，如果不解决抗微生物药物耐药性问题，经济成本估计将达到60至100万亿美元的经济产出。由于这种药物的盈利能力下降，市场上缺乏新的抗菌药物，这使抗生素耐药性问题更加严重。现代最成功的抗生素是氟喹诺酮类药物，如环丙沙星。然而，这些药物也受到抗菌素耐药性增加的影响，需要找到替代品。FQs通过靶向DNA旋切酶和/或DNA拓扑异构酶IV发挥作用，这些酶在细菌中是必需的，但在人类细胞中却不存在。我们正在研究同样针对gyrase的化合物，但它们以不同的方式起作用，从而可以避免与FQs产生交叉抗性。目前，由于毒性等问题，这些化合物不适合作为人类抗生素。利用计算方法、合成化学、生化/生物物理研究、微生物学和毒理学评估以及结构工作，我们的目标是开发新的类似药物的化合物（即在溶解度、效力和大小方面具有良好的特性），这些化合物既保留其抗菌功效，又具有药物先导物所需的其他特性，包括低毒性。在该项目结束时，我们的目标是确定一系列新的抗菌药物线索，这些线索将为后续开发带来可观的前景。

Antimicrobial resistance (AMR) is probably the biggest current threat to human health. Recent estimates (O'Neill Report, 2016) suggest that 10 million people a year could die as a result of AMR by 2050. In addition, the economic cost has been estimated to be between 60 and 100 trillion USD worth of economic output, if antimicrobial drug resistance is not tackled. This AMR problem is compounded by the lack of new antibacterial agents coming onto the market, caused by the loss of profitability of such drugs. Amongst the most successful groups of antibiotics of modern times are the fluoroquinolones (FQs), such as ciprofloxacin. However, these too are subject to increasing AMR and alternatives need to be found. FQs act by targeting DNA gyrase and/or DNA topoisomerase IV, enzymes that are essential in bacteria but absent from human cells. We are working with compounds that also target gyrase but that act in a different way such that cross resistance with FQs can be avoided. Currently these compounds are not suitable as human antibiotics due to issues such as toxicity. Using computational methods, synthetic chemistry, biochemical/biophysical studies, microbiological and toxicology evaluation, and structural work, we aim to develop new, drug-like compounds (i.e. with favourable properties in terms of solubility, potency and size) that retain their antibacterial efficacy but which also have other properties required for drug leads, including low toxicity. At the end of this project, we aim to have identified a new series of antibacterial drug leads that will hold considerable promise for subsequent development.