The molecular basis of the action of the antibiotic simocyclinone D8 on DNA gyrase

抗生素西莫环酮 D8 对 DNA 旋转酶作用的分子基础

• 批准号: BB/I002049/1
• 负责人: Anthony Maxwell
• 金额: $ 58.33万
• 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: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI002049%2F1
• 关键词: molecular; basis; action; antibiotic; simocyclinone

Antibiotics are drugs used to treat infections caused by bacteria. Most antibiotics are natural products and many of these are derived originally from soil bacteria (called Actinomycetes). Although antibiotics have generally been very successful over the last 40 years or so, recent years have seen the emergence of antibiotic-resistant bacteria (the so-called 'Superbugs'). These include MRSA (methicillin-resistant Staphylococcus aureus) and C. difficule, which have led to significant concern, particularly in UK hospitals. Unfortunately fewer new antibiotics are coming on the market, raising the prospect of untreatable bacteria diseases in the future. Simocyclinone D8 is a relatively recently discovered antibiotic that is not currently in clinical use. We have been able to show that it targets an enzyme in bacteria (DNA gyrase) by a novel mechanism. We aim to understand this mechanism of action in detail in order to reveal principles of drug-target interaction that will be applicable to other systems. We anticipate that this knowledge will provide information that will be used, particularly in the pharmaceutical industry, in the design of more-potent, more-specific antibiotics that will avoid the resistance problems that we are currently encountering.

抗生素是用于治疗细菌引起的感染的药物。大多数抗生素是天然产物，其中许多最初来自土壤细菌（称为放线菌）。虽然抗生素在过去40年左右的时间里普遍非常成功，但近年来出现了耐药性细菌（所谓的“超级细菌”）。这些包括MRSA（耐甲氧西林金黄色葡萄球菌）和C。困难，这引起了人们的严重担忧，特别是在英国医院。不幸的是，市场上新的抗生素越来越少，这增加了未来无法治愈的细菌性疾病的前景。Simocyclinone D8是一种相对较新发现的抗生素，目前尚未在临床上使用。我们已经能够证明它通过一种新的机制靶向细菌中的一种酶（DNA促旋酶）。我们的目标是详细了解这种作用机制，以揭示适用于其他系统的药物-靶标相互作用的原理。我们预计，这些知识将提供信息，特别是在制药行业，在设计更有效，更具体的抗生素，将避免我们目前遇到的耐药性问题。

项目成果

A new crystal structure of the bifunctional antibiotic simocyclinone D8 bound to DNA gyrase gives fresh insight into the mechanism of inhibition.

• DOI: 10.1016/j.jmb.2014.02.017
• 发表时间: 2014-05-15
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Hearnshaw SJ;Edwards MJ;Stevenson CE;Lawson DM;Maxwell A
• 通讯作者: Maxwell A

A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents

• DOI: 10.1039/c6md00229c
• 发表时间: 2016-01-01
• 期刊: MEDCHEMCOMM
• 作者: Austin, Michael J.;Hearnshaw, Stephen J.;Searcey, Mark
• 通讯作者: Searcey, Mark

SimC7 Is a Novel NAD(P)H-Dependent Ketoreductase Essential for the Antibiotic Activity of the DNA Gyrase Inhibitor Simocyclinone.

• DOI: 10.1016/j.jmb.2015.03.019
• 发表时间: 2015-06-19
• 期刊: JOURNAL OF MOLECULAR BIOLOGY
• 影响因子: 5.6
• 作者: Schaefer, Martin;Le, Tung B. K.;Hearnshaw, Stephen J.;Maxwell, Anthony;Challis, Gregory L.;Wilkinson, Barrie;Buttner, Mark J.
• 通讯作者: Buttner, Mark J.

Structural insights into simocyclinone as an antibiotic, effector ligand and substrate.

• DOI: 10.1093/femsre/fux055
• 发表时间: 2018-01-01
• 期刊: FEMS microbiology reviews
• 影响因子: 11.3
• 作者: Buttner MJ;Schäfer M;Lawson DM;Maxwell A
• 通讯作者: Maxwell A