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

探索 DNA 旋转酶和 DNA 拓扑异构酶 IV 中的新型结合袋以解决抗生素耐药性问题

• 批准号: BB/V006983/1
• 负责人: Anthony Maxwell
• 金额: $ 64.25万
• 依托单位: John Innes Centre
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FV006983%2F1
• 关键词: Exploring; novel; binding; pockets; DNA; Exploring; novel; binding; pockets; DNA

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.

抗菌耐药性（AMR）可能是当前对人类健康的最大威胁。最近的估计（2016年O'Neill报告）表明，到2050年，AMR每年可能死亡1000万人。此外，如果未解决抗菌药物耐药性，则估计经济成本在60至100万亿美元之间的经济产出。由于缺乏这种药物盈利能力造成的新抗菌剂，这种AMR问题更加复杂。在现代最成功的抗生素中，有氟喹诺酮（FQS），例如环丙沙星。但是，这些也可能会增加AMR，并且需要找到替代方案。 FQS通过靶向DNA陀螺酶和/或DNA拓扑异构酶IV，该酶在细菌中必不可少但没有人类细胞中。我们正在使用靶向回旋酶但以不同方式起作用的化合物，因此可以避免与FQS的交叉电阻。目前，由于毒性等问题，这些化合物不适合作为人类抗生素。使用计算方法，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性工作，我们旨在开发新的类似药物的化合物（即具有溶解度，效能和尺寸方面具有良好的特性），以保留其抗生细菌效率，但对药物的毒素含量也低，包括其他毒品的毒性。在该项目结束时，我们的目标是确定一系列新的抗菌药物铅，这些抗菌药物将对随后的发展保持巨大的希望。