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

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.

抗生素耐药性（AMR）可能是目前对人类健康的最大威胁。最近的估计（奥尼尔报告，2016）表明，到2050年，每年可能有1000万人死于AMR。此外，如果不解决抗生素耐药性问题，经济成本估计为60至100万亿美元的经济产出。由于缺乏新的抗菌药物进入市场，这类药物的盈利能力丧失，使AMR问题更加复杂。现代最成功的抗生素组是氟喹诺酮类（FQs），如环丙沙星。然而，这些也受到AMR增加的影响，需要找到替代品。FQs通过靶向DNA促旋酶和/或DNA拓扑异构酶IV发挥作用，这些酶在细菌中是必需的，但在人类细胞中不存在。我们正在研究也靶向促旋酶的化合物，但其作用方式不同，因此可以避免与FQs的交叉耐药性。目前，这些化合物由于毒性等问题不适合作为人类抗生素。使用计算方法，合成化学，生物化学/生物物理研究，微生物学和毒理学评价以及结构工作，我们的目标是开发新的药物样化合物（即在溶解度，效力和大小方面具有有利的特性），保留其抗菌功效，但也具有药物先导所需的其他特性，包括低毒性。在这个项目结束时，我们的目标是确定一系列新的抗菌药物，这将为后续的开发带来相当大的希望。

项目成果

De novo design of type II topoisomerase inhibitors as potential antimicrobial agents targeting a novel binding region.

• DOI: 10.1039/d2md00049k
• 发表时间: 2022-07-20
• 期刊: RSC medicinal chemistry
• 影响因子: 4.1