Novel hybrid anti-MRSA antibiotics from manipulation of the mupirocin and thiomarinol biosynthetic pathways
莫匹罗星和thiomarinol生物合成途径的新型混合抗MRSA抗生素
基本信息
- 批准号:BB/I014373/1
- 负责人:
- 金额:$ 66.86万
- 依托单位:
- 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:
- 关键词:
项目摘要
For centuries mankind has used natural products in crude extracts from plants and fungi as well as in purified form as remedies to cure disease. Many such compounds have become house-hold names e.g. the penicillin antibiotics which kill bacteria. Natural products and their derivatives are still vitally important, representing a large proportion of drugs currently on the market. Understanding of how they are made in nature (biosynthesis) opens new opportunities in drug development. Polyketides, an important class of natural products, exhibit huge diversity of structures and biological activities e.g. antibacterial, antifungal and anticancer. Mupirocin, a mixture of four pseudomonic acids (PAs) isolated from the bacterium Pseudomonas fluorescens, is an example of a polyketide with an intriguing biosynthetic pathway. It is clinically important, being active against MRSA (methicillin resistant Staphylococcus aureus), but is only used topically due to its instability. In an adventurous interdisciplinary programme involving microbial molecular genetics, biochemistry and chemistry we have learnt much about PA biosynthesis which has many intriguing features but requires further study for a full understanding. In our new programme we aim to create new hybrids between molecules with proven biological activity to increase the chance of developing new antibiotics that can overcome problems associated with resistance. The thiomarinol family of antibacterial compounds produced naturally by marine bacteria consists of two elements: one, a PA is similar (but not identical) to mupirocin; the other is like the core of a less well understood compound, holomycin (more generically called pyrrothine). Our recent studies confirm that the genes responsible for making thiomarinol resemble both those for mupirocin in the bacterium Pseudomonas fluorescens and an as yet un-characterised gene cluster from the filamentous bacterium Streptomyces clavuligerus which we can now assign to holomycin biosynthesis. From this new gene cluster we can deduce that holomycin is produced by an unusual form of a protein factory called a non-ribosomal peptide synthetase and starts by joining two molecules of the amino acid cysteine. We have shown that both elements of thiomarinol are made separately and then linked together. Using mutants we can join holomycin to mupirocin itself allowing it to overcome mupirocin resistance in its target enzyme, isoleucyl tRNA synthetase. This therefore identifies a way that an existing antibiotic can be modified to overcome the resistance that is spreading clinically. One of our aims is to use genetic manipulation to replace the pyrrothine by other chemical species to create favourable new properties. We will use diverse gene clusters to determine what can be joined to PA and with what biological activity against a range of current superbugs and other important medically important targets. We will also feed chemically synthesised substrates to mutants that do not make the pyrrothine in order to generate families of new compounds. Also, because the genes that make the pyrrothine are unusual we will study them in detail in case their properties teach us new ways to build small molecules that could become part of novel antibiotics. It is also vital to understand how key steps in mupirocin and thiomarinol biosynthesis are controlled - particularly the timing and mechanism of specific biotransformations. The mupirocin biosynthetic pathway is an archetype of its class and is well placed to answer a number of general questions that apply to related systems. Finally we will study the interaction of the antibiotics with their target enzymes, modelling their structures and docking the small antibiotics with the proteins to predict which parts of the molecules are important and why. This should help direct desirable modifications that will create novel biological properties effective against key bacterial pathogens
几个世纪以来,人类一直使用植物和真菌的粗提取物以及纯化形式的天然产物来治疗疾病。许多这类化合物已成为家喻户晓的名字,例如杀死细菌的青霉素抗生素。天然产品及其衍生物仍然至关重要,在目前市场上的药物中占很大比例。了解它们是如何在自然界中制造的(生物合成)为药物开发开辟了新的机会。聚酮类化合物是一类重要的天然产物,具有多种结构和生物活性,如抗菌、抗真菌和抗癌等。莫匹罗星是从荧光假单胞菌中分离出来的四种假单胞酸(PAs)的混合物,是具有有趣生物合成途径的聚酮的一个例子。它对MRSA(耐甲氧西林金黄色葡萄球菌)有活性,具有重要的临床意义,但由于其不稳定,只能局部使用。在一个涉及微生物分子遗传学、生物化学和化学的跨学科项目中,我们学到了很多关于PA生物合成的知识,它有许多有趣的特征,但需要进一步的研究才能充分理解。在我们的新计划中,我们的目标是在具有已证实的生物活性的分子之间创造新的杂交体,以增加开发能够克服与耐药性有关的问题的新抗生素的机会。由海洋细菌自然产生的抗菌化合物硫代氨基酚家族由两个元素组成:一是PA与莫匹罗星相似(但不完全相同);另一种就像一种不太为人所知的化合物的核心,全息霉素(更一般地被称为pyrrothine)。我们最近的研究证实,负责制造硫马油醇的基因类似于荧光假单胞菌中的莫比罗辛基因,也类似于丝状细菌链霉菌中的一个尚未表征的基因簇,我们现在可以将其分配给全息霉素的生物合成。从这个新的基因簇中,我们可以推断出,全息霉素是由一种叫做非核糖体肽合成酶的不寻常的蛋白质工厂产生的,它从连接两个氨基酸半胱氨酸分子开始。我们已经证明硫马油醇的两种元素是分开制造的,然后连接在一起。利用突变体,我们可以将全霉素与莫匹罗星本身结合,使其在靶酶异亮基tRNA合成酶中克服对莫匹罗星的耐药性。因此,这确定了一种可以修改现有抗生素以克服临床传播的耐药性的方法。我们的目标之一是利用基因操作用其他化学物质取代吡咯氨酸,以创造有利的新特性。我们将使用不同的基因簇来确定哪些可以与PA结合,以及与哪些生物活性结合,以对抗一系列当前的超级细菌和其他重要的医学目标。我们还将化学合成的底物喂给不产生pyropythine的突变体,以产生新的化合物家族。此外,由于产生pyrothine的基因是不寻常的,我们将详细研究它们,以防它们的特性教会我们构建小分子的新方法,这些小分子可能成为新型抗生素的一部分。了解如何控制莫匹罗星和硫代马油醇生物合成的关键步骤——特别是特定生物转化的时间和机制也是至关重要的。莫匹罗星生物合成途径是其类的原型,很好地回答了一些适用于相关系统的一般问题。最后,我们将研究抗生素与其靶酶的相互作用,模拟它们的结构,并将小抗生素与蛋白质对接,以预测分子的哪些部分是重要的以及为什么重要。这应该有助于指导理想的修改,将创造新的生物特性有效对抗关键的细菌病原体
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics
选定的突变揭示了莫匹罗星和硫代马林醇抗生素生物合成中的新中间体
- DOI:10.1002/ange.201611590
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Gao S
- 通讯作者:Gao S
Minimum Information about a Biosynthetic Gene cluster.
- DOI:10.1038/nchembio.1890
- 发表时间:2015-09
- 期刊:
- 影响因子:14.8
- 作者:Medema MH;Kottmann R;Yilmaz P;Cummings M;Biggins JB;Blin K;de Bruijn I;Chooi YH;Claesen J;Coates RC;Cruz-Morales P;Duddela S;Düsterhus S;Edwards DJ;Fewer DP;Garg N;Geiger C;Gomez-Escribano JP;Greule A;Hadjithomas M;Haines AS;Helfrich EJ;Hillwig ML;Ishida K;Jones AC;Jones CS;Jungmann K;Kegler C;Kim HU;Kötter P;Krug D;Masschelein J;Melnik AV;Mantovani SM;Monroe EA;Moore M;Moss N;Nützmann HW;Pan G;Pati A;Petras D;Reen FJ;Rosconi F;Rui Z;Tian Z;Tobias NJ;Tsunematsu Y;Wiemann P;Wyckoff E;Yan X;Yim G;Yu F;Xie Y;Aigle B;Apel AK;Balibar CJ;Balskus EP;Barona-Gómez F;Bechthold A;Bode HB;Borriss R;Brady SF;Brakhage AA;Caffrey P;Cheng YQ;Clardy J;Cox RJ;De Mot R;Donadio S;Donia MS;van der Donk WA;Dorrestein PC;Doyle S;Driessen AJ;Ehling-Schulz M;Entian KD;Fischbach MA;Gerwick L;Gerwick WH;Gross H;Gust B;Hertweck C;Höfte M;Jensen SE;Ju J;Katz L;Kaysser L;Klassen JL;Keller NP;Kormanec J;Kuipers OP;Kuzuyama T;Kyrpides NC;Kwon HJ;Lautru S;Lavigne R;Lee CY;Linquan B;Liu X;Liu W;Luzhetskyy A;Mahmud T;Mast Y;Méndez C;Metsä-Ketelä M;Micklefield J;Mitchell DA;Moore BS;Moreira LM;Müller R;Neilan BA;Nett M;Nielsen J;O'Gara F;Oikawa H;Osbourn A;Osburne MS;Ostash B;Payne SM;Pernodet JL;Petricek M;Piel J;Ploux O;Raaijmakers JM;Salas JA;Schmitt EK;Scott B;Seipke RF;Shen B;Sherman DH;Sivonen K;Smanski MJ;Sosio M;Stegmann E;Süssmuth RD;Tahlan K;Thomas CM;Tang Y;Truman AW;Viaud M;Walton JD;Walsh CT;Weber T;van Wezel GP;Wilkinson B;Willey JM;Wohlleben W;Wright GD;Ziemert N;Zhang C;Zotchev SB;Breitling R;Takano E;Glöckner FO
- 通讯作者:Glöckner FO
Current trends in Bioinformatics: An Insight
生物信息学的当前趋势:洞察
- DOI:10.1007/978-981-10-7483-7_7
- 发表时间:2018
- 期刊:
- 影响因子:0
- 作者:Farmer R
- 通讯作者:Farmer R
Back Cover: Selected Mutations Reveal New Intermediates in the Biosynthesis of Mupirocin and the Thiomarinol Antibiotics (Angew. Chem. Int. Ed. 14/2017)
封底:选定的突变揭示了莫匹罗星和硫代马林醇抗生素生物合成中的新中间体(Angew. Chem. Int. Ed. 14/2017)
- DOI:10.1002/anie.201702123
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Gao S
- 通讯作者:Gao S
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Christopher Thomas其他文献
Motion modelling and motion compensated reconstruction of tumours in cone-beam computed tomography
锥形束计算机断层扫描中肿瘤的运动建模和运动补偿重建
- DOI:
10.1109/mmbia.2012.6164764 - 发表时间:
2012 - 期刊:
- 影响因子:0
- 作者:
James Martin;J. McClelland;Christopher Thomas;Kate Wildermuth;D. Landau;S. Ourselin;D. Hawkes - 通讯作者:
D. Hawkes
An Investigation Into the Relationship Between Maximum Isometric Strength and Vertical Jump Performance
最大等长力量与垂直弹跳性能关系的研究
- DOI:
- 发表时间:
2015 - 期刊:
- 影响因子:3.2
- 作者:
Christopher Thomas;Paul A. Jones;J. Rothwell;C. Chiang;P. Comfort - 通讯作者:
P. Comfort
Context as Content in Urban Teacher Education
作为城市教师教育内容的情境
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
P. Williamson;Xornam S. Apedoe;Christopher Thomas - 通讯作者:
Christopher Thomas
Managing Lymphedema in Fracture Care: Current Concepts and Treatment Principles.
骨折护理中的淋巴水肿管理:当前概念和治疗原则。
- DOI:
10.5435/jaaos-d-19-00722 - 发表时间:
2020 - 期刊:
- 影响因子:0
- 作者:
Christopher Thomas;Jessica T. Le;E. Benson - 通讯作者:
E. Benson
An up-to-date knowledge-based literature search and exploration framework for focused bioscience domains
针对生物科学重点领域的最新的基于知识的文献检索和探索框架
- DOI:
10.1145/2110363.2110396 - 发表时间:
2012 - 期刊:
- 影响因子:4.5
- 作者:
Ramakanth Kavuluru;Christopher Thomas;A. Sheth;Victor Chan;Wenbo Wang;Alan Smith;Armando Soto;Amy Walters - 通讯作者:
Amy Walters
Christopher Thomas的其他文献
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{{ truncateString('Christopher Thomas', 18)}}的其他基金
Simone Weil Research Network United Kingdom
英国西蒙娜·韦尔研究网络
- 批准号:
AH/W000083/1 - 财政年份:2021
- 资助金额:
$ 66.86万 - 项目类别:
Research Grant
Plasmid biology underpinning development of a novel plasmid displacement technology to eliminate antibiotic resistance genes
质粒生物学支持开发新型质粒置换技术以消除抗生素抗性基因
- 批准号:
BB/S003533/1 - 财政年份:2018
- 资助金额:
$ 66.86万 - 项目类别:
Research Grant
Developing the Mupirocin QS system of P fluorescens into an efficient and economical way to control industrial production of high value products
将荧光磷莫匹罗星 QS 系统开发为控制高价值产品工业生产的高效且经济的方法
- 批准号:
BB/M028739/1 - 财政年份:2015
- 资助金额:
$ 66.86万 - 项目类别:
Research Grant
13TSB_SynBio: Synthetic biology to improve antibiotic production
13TSB_SynBio:利用合成生物学提高抗生素产量
- 批准号:
BB/L004453/1 - 财政年份:2013
- 资助金额:
$ 66.86万 - 项目类别:
Research Grant
HYDROMAL: Hydro-dynamic drivers of malaria transmission hazard in Africa
水力:非洲疟疾传播危险的水力驱动因素
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NE/H022740/1 - 财政年份:2011
- 资助金额:
$ 66.86万 - 项目类别:
Research Grant
Mapping Ecosystem Services for Agricultural Improvement and Human Health in Sub-Saharan Africa
绘制撒哈拉以南非洲农业改良和人类健康生态系统服务图
- 批准号:
NE/I004351/1 - 财政年份:2010
- 资助金额:
$ 66.86万 - 项目类别:
Research Grant
Biosynthesis of polyketide antibiotic mupirocin by Pseudomonas fluorescens
荧光假单胞菌生物合成聚酮类抗生素莫匹罗星
- 批准号:
BB/E021611/1 - 财政年份:2007
- 资助金额:
$ 66.86万 - 项目类别:
Research Grant
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