A pipeline technology for discovery of new antibiotics from Streptomyces

点击翻译按钮获取中文摘要

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.