A pipeline technology for discovery of new antibiotics from Streptomyces

从链霉菌中发现新抗生素的管道技术

• 批准号: BB/H023747/1
• 负责人: Paul Dyson
• 金额: $ 13.33万
• 依托单位: Swansea University
• 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%2FH023747%2F1
• 关键词: pipeline; technology; discovery; new; antibiotics

It is inescapable that modern medicine is faced with a severe challenge in the form of 'Superbugs' - disease-causing bacteria that are resistant to front-line antibiotics. The antibiotic era in medicine has spanned the last 70 years with the first drugs, penicillin and streptomycin, being introduced in the late 1940's. A dramatic reduction in fatalities associated with bacterial infections followed, as did the discovery of many new antibiotics, reaching a peak in the 1980's. Since then, there has been a dramatic decline in new antibiotic discovery, and an increase both in the incidence of resistance to front-line antibiotics and in patient fatalities due to infections by these resistant bacteria. The majority of antibiotics are produced by soil bacteria called Streptomyces. Recent genome sequencing projects with representative species of these bacteria have revealed that they possess many 'cryptic' antibiotic biosynthetic pathways; that is they have the genetic potential to produce many more antibiotics than previously realised. An outcome of a European collaborative research project, ActinoGEN, coordinated by Dyson, indicates that these cryptic pathways are not genetic relics but can be activated to direct production of new antibiotics. Consequently we can now interpret the last 70 years as an initial period during which 'low-hanging fruit', our current front-line antibiotics, were discovered. Thereafter, the success in discovery has declined. A current challenge is now to harvest the plentiful higher-hanging fruit, the products of the cryptic pathways, and extend the range of antibiotics that can be used in medicine. The ways to do this are at present very time-consuming, dependent on first obtaining and analysing the genome sequences of Streptomyces species, before genetic engineering to activate a cryptic pathway. This proposal addresses a technological gap by devising a means of inexpensive strain manipulation coupled with high-throughput screening of extensive Streptomyces strain libraries to discover new antibiotic products of cryptic pathways. The strain manipulations involve rapid and synergistic approaches to activate and over-produce new antibiotics. To demonstrate a proof-of-principle, having obtained manipulated strains over-producing a novel antibiotic, we will then analyse the antibiotic and determine the cryptic biosynthetic pathway that directs its synthesis. Successful demonstration of the technology will subsequently lead to its adoption to discover new antibiotics produced in large strain collections, in collaboration with industrial partners from the pharmaceutical/biotech sector.

不可避免的是，现代医学正面临着“超级细菌”的严峻挑战。“超级细菌”是一种对一线抗生素具有耐药性的致病细菌。在过去的70年里，医学上的抗生素时代跨越了第一批药物，青霉素和链霉素，在20世纪40年代末被引入。随着许多新抗生素的发现，与细菌感染相关的死亡率急剧下降，并在20世纪80年代达到顶峰。自那时以来，新抗生素的发现急剧减少，对一线抗生素的耐药性发生率和因这些耐药细菌感染而导致的患者死亡人数都有所增加。大多数抗生素是由一种叫做链霉菌的土壤细菌产生的。最近对这些细菌的代表性物种进行的基因组测序项目表明，它们具有许多“隐式”抗生素生物合成途径；也就是说，它们具有比以前认识到的生产更多抗生素的遗传潜力。一项由Dyson协调的欧洲合作研究项目ActinoGEN的结果表明，这些隐藏的途径不是遗传遗迹，而是可以被激活来指导新抗生素的生产。因此，我们现在可以将过去的70年解释为“唾手可得的果实”，即我们目前的一线抗生素被发现的初始时期。此后，发现的成功率下降了。目前面临的挑战是收获大量的高挂果实，即隐性途径的产物，并扩大可用于医学的抗生素的范围。目前实现这一目标的方法非常耗时，依赖于首先获得和分析链霉菌物种的基因组序列，然后通过基因工程激活一个隐藏的途径。该建议通过设计一种廉价的菌株操作方法以及对广泛链霉菌菌株库的高通量筛选来发现新的隐途径抗生素产品，从而解决了技术差距。菌株操作涉及快速和协同的方法来激活和过量生产新的抗生素。为了证明原理证明，在获得过量生产新型抗生素的操纵菌株后，我们将分析抗生素并确定指导其合成的隐生物合成途径。该技术的成功演示随后将导致其与制药/生物技术部门的工业伙伴合作，用于发现在大型菌株收集中生产的新抗生素。

项目成果

Reference Module in Biomedical Sciences

生物医学科学参考模块

• DOI: 10.1016/b978-0-12-801238-3.02306-0
• 发表时间: 2014
• 作者: Dyson P

Streptomyces Isolates from the Soil of an Ancient Irish Cure Site, Capable of Inhibiting Multi-Resistant Bacteria and Yeasts

从古代爱尔兰治疗地点的土壤中分离出的链霉菌，能够抑制多重耐药细菌和酵母

• DOI: 10.3390/app11114923
• 发表时间: 2021
• 期刊: Applied Sciences
• 作者: Quinn G