Structural and Mechanistic Investigations of Antibiotic Production in Bacteria

细菌产生抗生素的结构和机制研究

• 批准号: BB/R007853/1
• 负责人: Chris Willis
• 金额: $ 92.3万
• 依托单位: University of Bristol
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FR007853%2F1
• 关键词: Structural; Mechanistic; Investigations; Antibiotic; Production

There is an indisputable problem of antibiotic resistance and an urgent need for the discovery and development of new antibiotics that are cost effective to produce. In February 2017, the World Health Organisation (WHO) published its first ever list of antibiotic resistant priority pathogens that pose serious risks to human health. This list includes high priority targets such as the well-publicised methicillin resistant Staphylococcus aureus (MRSA) and there is clear recognition that urgent action and research into new antibiotics is required. However against this alarming headline, a drop in investment in research and development into new antibiotics has led to a dramatic fall in the number of new drugs being discovered and a reduction in knowledge and expertise that is capable of delivering them.Natural products and their derivatives have, and will continue to be, an important source of these antibiotics that are critical for human and animal health. Polyketides are a family of natural products which include high value compounds including antibiotics. They are derived from a wide range of sources including bacteria and fungi. Over the last fifty years some understanding of the remarkably complex and diverse ways in which antibiotics are synthesised in Nature has been gained. Whilst bacteria and fungi might be viewed as simple organisms, they arguably outperform the world's best synthetic chemists in terms of their elegance and efficiency and it is this power we wish to harness. By fully understanding nature's biosynthetic machinery we can engineer pathways to deliver new bioactive compounds.It turns out that many antibiotics are made by a series of chemical reactions catalysed by megaprotein assemblies that act as nano-scale factories inside the microbe. Simple organic molecules are activated and loaded at one end, joined together and then released as completed (usually elaborate) products at the other end. The nano-factories join the simple building blocks on an assembly line of individual modules, akin to a group of robots performing operations in vehicle manufacture. The chemical structure of each antibiotic is thus determined by the enzymes present at each stage of the assembly line, the blueprint being the biosynthetic gene cluster. We understand some rules for building these factories and can rearrange the order of modules to produce new compounds, but sometimes this just breaks the assembly line, or produces an unexpected compound. This reveals we don't truly understand how they have evolved to fit together and we do not know all of the chemical steps required. Our aim is to investigate two different "factories" that produce anti-MRSA antibiotics. The first produces mupirocin, which is used commercially but is restricted to topical use and in nasal sprays because of its instability. The second is thiomarinol, structurally related to mupirocin, but has features that might lead to wider applications. A substantial number of important biosynthetic steps are not fully understood in both of these systems. Combining the expertise of chemists, biochemists, structural biologists and molecular modellers we will elucidate these steps which could lead to a more stable version of mupirocin. We will also use these systems to answer quite general questions so we can build new pathways to novel compounds in a rational way.

抗生素耐药性和迫切需要发现和开发新的抗生素的问题，这些抗生素的生产具有成本效益。 2017年2月，世界卫生组织（WHO）发布了有史以来第一个抗生素抗生素优先病原体清单，对人类健康构成了严重风险。该列表包括高优先级目标，例如耐甲氧西林的金黄色葡萄球菌（MRSA），并且清楚地认识到需要对新抗生素进行紧急行动和研究。然而，在这个令人震惊的标题上，对新抗生素的研究和开发投资下降导致发现的新药数量急剧下降，知识和专业知识的减少，能够提供它们的知识和专业知识。自然产物及其衍生物将继续是这些对人类和动物健康至关重要的重要来源。聚酮化合物是一系列天然产品，其中包括包括抗生素在内的高价值化合物。它们来自包括细菌和真菌在内的广泛来源。在过去的五十年中，已经获得了对自然界中抗生素合成的非常复杂和多样化的方式的一些理解。尽管细菌和真菌可能被视为简单的生物，但就其优雅和效率而言，它们可以说优于世界上最好的合成化学家，这就是我们希望利用的这种力量。通过完全了解大自然的生物合成机械，我们可以设计途径来传递新的生物活性化合物。事实证明，许多抗生素是由一系列由巨型蛋白组件催化的化学反应制成的，这些化学反应是巨型机构中的纳米级工厂。简单的有机分子在一端被激活并加载，并在另一端完成（通常是精心制作）的产品，然后释放在一起。纳米因子将简单的构件在单个模块的组装线上加入，类似于一组在车辆制造中执行操作的机器人。因此，每种抗生素的化学结构由组装线的每个阶段的酶确定，蓝图是生物合成基因簇。我们了解一些建立这些工厂的规则，并可以重新排列模块以产生新化合物的顺序，但是有时这只是打破了装配线，或产生意外的化合物。这表明我们并不真正了解它们如何发展在一起，并且我们不知道所需的所有化学步骤。我们的目的是研究产生抗MRSA抗生素的两种不同的“工厂”。第一个产生的穆匹洛毒素在商业上用于商业使用，但由于其不稳定性而仅限于局部用途和鼻喷雾剂。第二个是硫瘤，与莫皮罗辛结构相关，但具有可能导致更广泛应用的特征。在这两个系统中，尚未完全了解大量重要的生物合成步骤。结合了化学家，生物化学家，结构生物学家和分子模块的专业知识，我们将阐明这些步骤，这些步骤可能导致更稳定的莫皮罗辛。我们还将使用这些系统来回答相当一般的问题，以便我们可以以合理的方式为新颖化合物建立新的途径。

项目成果

Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin

程序化迭代控制抗生素莫匹罗星壬酸侧链的组装

• DOI: 10.1002/ange.202212393
• 发表时间: 2022
• 期刊: Angewandte Chemie
• 作者: Winter A

A Rieske oxygenase/epoxide hydrolase-catalysed reaction cascade creates oxygen heterocycles in mupirocin biosynthesis

• DOI: 10.1038/s41929-018-0183-5
• 发表时间: 2018-12-01
• 期刊: NATURE CATALYSIS
• 影响因子: 37.8
• 作者: Wang, Luoyi;Parnell, Alice;Willis, Christine L.
• 通讯作者: Willis, Christine L.

A Priming Cassette Generates Hydroxylated Acyl Starter Units in Mupirocin and Thiomarinol Biosynthesis.

引发盒在莫匹罗星和硫代马林醇生物合成中生成羟基化酰基起始单元。

• DOI: 10.1021/acschembio.9b00969
• 发表时间: 2020
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Walker PD

Programmed Iteration Controls the Assembly of the Nonanoic Acid Side Chain of the Antibiotic Mupirocin.

• DOI: 10.1002/anie.202212393
• 发表时间: 2022-12-12
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Winter, Ashley J.;Rowe, Matthew T.;Weir, Angus N. M.;Akter, Nahida;Mbatha, Sbusisiwe Z.;Walker, Paul D.;Williams, Christopher;Song, Zhongshu;Race, Paul R.;Willis, Christine L.;Crump, Matthew P.
• 通讯作者: Crump, Matthew P.

Structure and Function of the a-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase.

莫匹罗星聚酮合酶的α-羟基化双模块的结构和功能。

• DOI: 10.1002/ange.202312514
• 发表时间: 2023
• 期刊: Angewandte Chemie (Weinheim an der Bergstrasse, Germany)
• 作者: Winter AJ