Multiple drug resistant bacteria are a major threat to human health and a significant burden on already stretched medical budgets. This threat is predicted to increase in severity, and remedial actions of reducing antibiotic use in animal husbandry and limiting current prescribing activities for non-lethal human disease are both unlikely to reduce the danger in the short-term. Of major concern are antibiotic-resistant nosocomial infections. The economic and societal costs of these hospital-acquired infections are enormous: the UK National Health Service has estimated an annual cost of 1.5 billion € for extra patient care and that 5000 deaths result each year. In addition, the incidence of infection by multiple drug resistant strains of Mycobacterium tuberculosis, the causative agent of the tuberculosis, is rapidly increasing, particularly among the disadvantaged in society. Investment in R&D into antibiotic discovery by the major pharmaceutical companies has declined dramatically in the last 15 years as a perception has taken hold that easily obtained natural products may have been fully exploited. Hence conventional screening of natural products for new drugs is no longer considered economically worthwhile. Unfortunately, the downturn in drug discovery has coincided with a dramatic worldwide increase in the incidence of resistance to all the antibiotics currently used in medicine.

The aim of this proposal is to combine new functional genomic technologies with chemical analysis in an integrated multidisciplinary approach both to exploit hitherto overlooked genetic resources for new antibiotics and, secondly, develop generic 'superhosts' to produce these new antibiotics in high yields. ActinoGEN proposes three parallel objectives to discover and develop new antibiotics based on exploiting the genetic resources of actinomycetes, hitherto the major source of existing antimicrobials. The first of these is to activate cryptic antibiotic biosynthetic pathways. Recent genome sequencing projects have revealed a genetic potential for actinomycetes to produce many more antibiotics than previously recognised. ActinoGEN will explore how different cryptic pathways can be activated and then determine the structures and activities of the resulting new antimicrobials. The second approach will rely on the discovery of new antibiotic biosynthetic pathways from diverse actinomycetes. The number of actinomycete species that have been isolated to date represents a small fraction of the total in the environment. ActinoGEN will exploit the untapped genetic resource of as yet uncultured species to obtain antibiotic biosynthetic gene clusters that can direct synthesis of new antimicrobials. A third route to new antimicrobials is by combinatorial biosynthesis. Biosynthetic genes from both new and existing pathways will be combined to direct synthesis of new antibiotics with predicted structures. The design of new hybrid molecules will be related to improving antimicrobial activity. A fourth major aim, underpinning the Drug Discovery objectives, is the engineering of generic Superhosts for antibiotic production. A rate-limiting step to developing a new antibiotic is yield improvement. Post-genomic analysis permits, for the first time, a concerted and holistic approach to engineering generic Superhosts for use in the production of high yields of a wide variety of antibiotics. As part of ActinoGEN, this complementary activity is vital to greatly accelerate the discovery and development of new drugs.

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