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Bacterial 'genome mining' brings novel antibiotic to light

Researchers in the Netherlands and the UK have discovered a novel antibiotic using a new tool to 'excavate' bacterial genomes. The findings, published in the journal Microbiology, could give the fight against multi-drug-resistant diseases a big boost. The study is the first to...

Researchers in the Netherlands and the UK have discovered a novel antibiotic using a new tool to 'excavate' bacterial genomes. The findings, published in the journal Microbiology, could give the fight against multi-drug-resistant diseases a big boost. The study is the first to use a new genome-mining technique on the common bacterium Streptomyces. The findings are an outcome of the ACTINOGEN ('Integrating genomics-based applications to exploit actinomycetes as a resource for new antibiotics') project, which was funded with roughly EUR 9.4 million through the 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6) to accelerate the drug discovery process by developing new approaches to exploit overlooked sources of novel antibiotics. Streptomyces is a genus of Actinobacteria found in soil and compost, and is used to produce most of the antibiotics of natural origin currently on the market. In 2002, genome sequencing of the species Streptomyces coelicolor revealed 12 'orphan' gene clusters whose function is not known, and which are not yet being used to make antibiotics. Since then, these genes have been the subject of intense research. In the new study, researchers from the University of Groningen in the Netherlands and the John Innes Centre in the UK looked for the products of the orphan gene cluster called cpk using a method of 'genome mining'. The team removed a part of the cluster, called scbR2, to inactivate the whole cpk cluster. By so doing, they were able to assess how scbR2 affects S. coelicolor's metabolism. By manipulating a regulatory gene, the researchers effectively activated the 'silent' gene cluster. The experiment uncovered a novel metabolite (the yellow-pigmented yCPK) as well as a new antibiotic substance, called abCPK. The new antibacterial compound happens to be effective against several bacterial strains including Escherichia coli. 'The strategy is a powerful and innovative way of searching for new antibiotic production capabilities in bacteria,' said Dr Eriko Takano of the University of Groningen. 'As bacterial infections previously considered as mild and easily curable are suddenly becoming lethal and completely unresponsive to all existing medication, it is crucial that new antibiotics are discovered at a sufficiently rapid rate.' The new findings may underpin an important route to the discovery of novel antibiotics or other useful compounds that are currently 'hidden' within the genomes of secondary metabolite-producing organisms such as filamentous fungi. 'There are several thousand other uncharacterised groups of genes that have been found recently in microbial genome sequences,' explained Dr Takano. 'This opens up a rich treasure trove of new potential drugs for clinical use.' ACTINOGEN, a pan-European consortium, combined scientific expertise from many disciplines to advance our understanding of antibiotic biosynthesis and, by so doing, to combat multi-drug-resistant pathogens.

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