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Lemon Holds the Secret to Manipulating Drug-Making Bugs

Researchers from the University of Georgia have found a method for transferring DNA into Streptomyces, the soil-borne bacteria from which drug companies currently prepare hundreds of antibiotics and some anticancer drugs. Their results, published online and in the May 22nd issue of the Proceedings of the National Academy of Sciences, open the way for scientists to engineer these organisms genetically¿an ability that should make it easier for pharmaceutical companies to develop new drugs.

Whereas other organisms can be easily manipulated¿Escherichia coli, for example, is the bacterial guinea pig for microbiologists¿Streptomyces is very reluctant to take up foreign DNA. For many years, scientists have used viruses called phages, which infect bacteria and transport bits of DNA into their hosts, to obtain genetically modified E. coli. This same tactic was useless for manipulating Streptomyces.

Janet Westpheling and two University of Georgia students, Julie Burke and David Schneider, suspected why this approach fails: the infected bacteria succumb to the viruses¿a phenomenon called superinfection killing. To test their hypothesis, they turned to citric acid, a substance that abounds in fruits such as lemons, limes, and oranges and can also decrease a phage's virulence. By adding tiny amounts of citric acid and lowering the temperature, the researchers found that they could in fact avoid lethal viral infection in the bacteria. More important, they succeeded in transferring a few marker genes from one strain of Streptomyces to another.

This finding could be a major breakthrough for speeding the development of new drugs. At least two dozen species of Streptomyces (hundreds are known to exist in nature) provide a major source of such drugs as streptomycin, choramphemicol and the anticancer drug bleomycin. But relatively little is known about their biology and how they make these molecules. Today most drug companies search for new antibiotics by testing thousands or millions of bacterial samples using costly and time-consuming procedures. And whereas pathogens become rapidly resistant to antibiotics, soil bacteria evolve too slowly to keep up. "There are many [new drugs] waiting to be developed if only the organisms that produce them could be manipulated," Westpheling says. "The ability to shuffle the genetic pathways for existing drugs may lead to [new compounds] for which there is no resistance."

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