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http://bmj.com/cgi/content/full/324/7347/1176/d

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Collections under which this article appears: Drugs: infections Basic sciences Genetics

BMJ 2002;324:1176 ( 11 May )
 

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Decoding of soil bacterium genome points way to new antibiotics

Susan Mayor London

A British consortium of scientists has decoded the complete genome sequence of Streptomyces coelicolor A3(2), a common soil bacterium that is the source of more than two thirds of the antibiotics in current use and the harmless relative of the causative organisms for tuberculosis, leprosy, and diphtheria.

The results have shown clusters of genes with the potential for producing new antibiotic agents.

S coelicolor is a soil dwelling, filamentous bacterium responsible for producing most of the natural antibiotics used in human and veterinary medicine today. Researchers working at the Wellcome Trust Sanger Institute, the John Innes Centre, and the University of Warwick have sequenced the organism's chromosome, which is more than eight million base pair long. Computer analysis of the genome predicted that it contained 7825 genes—the largest number of genes so far discovered in a bacterium—including an unprecedented number of regulatory genes, likely to be involved in responses to external stimuli and stresses (Nature 2002;417:141-7).

Lead author Dr Stephen Bentley, senior computer biologist at the Wellcome Trust Sanger Institute, Hinxton, near Cambridge, explained the clinical importance of the findings: "We found a lot of extra genes involved in the production of antibiotic-like compounds. Before the project, we had cloned only four genes for antibiotics produced by S coelicolor. We have found another 18 clusters of genes doing similar things."

He predicted: "In the future, we can shuffle these genes around to get Streptomyces to produce new compounds, including antibiotics, anticancer agents and immunosuppressants."

The John Innes Centre has been awarded £1.4m ($2m; €2.2m) to take the results of the genome sequencing project to the next stage, concentrating on 20 clusters of genes, which, it is hoped, code for new biologically active agents.

Sequencing of the S coelicolor genome was done by breaking it into 300 smaller fragments. Each of these was sequenced completely—to the last base—and the sequences of the fragments were then pieced back together. Sequencing began in 1997 and cost £2m, paid for by the Biotechnology and Biological Research Council and the Wellcome Trust.

Sequences were released into the public domain, on the Sanger Centre website, as soon as they became available, and there is no intention to limit use of the genome. Results showed that during the evolution of S coelicolor, its chromosome had acquired the ability to replicate in a linear form and had expanded by lateral acquisition and internal duplication of DNA.

This expansion provided a large number of genes, allowing the organism to develop a more complex life cycle and to detect and respond to external stimuli by producing previously uncharacterised enzymes. These enzymes are the potential starting points for the development of new medicines.

In addition, the sequence showed many features common to Streptomyces and related organisms causing human diseases. An ancient syteny was found between the central core of the chromosome and the whole chromosomes of pathogens Mycobacterium tuberculosis and Corynebacterium diphtheriae.

It is hoped that further investigation will provide new insights into their pathophysiology.
 
 

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