May 17, 2001 ATHENS, Ga. -- Researchers at the University of Georgia have, for the first time, successfully transferred DNA into genetically uncharacterized species of the important bacterium Streptomyces. The system is based on the use of phages (bacterial viruses) that infect these bacteria to transfer DNA from the host they are grown on to a recipient they later infect.
This procedure has several important advantages over current technology and will make it far easier (an in some cases possible) for pharmaceutical companies to develop Streoptomyces-based antibiotics and anti-cancer drugs. Results of the study were published online today in the Proceedings of the National Academy of Sciences. The print version of the research will be published on May 22.
“This will allow for the first time, for example, the study and manipulation of the bleomycin biosynthetic pathway in the producing organism. Bleomycin is an important anti-cancer chemotherapeutic drug that has so far been completely refractory to genetic manipulation,” said Dr. Janet Westpheling, a UGA geneticist and leader of the research team. “We anticipate that the ability to get DNA into this strain of Streptomyces will lead to the production of novel bleomycins.”
Westpheling, who reported on the discovery at an international meeting in Singapore in late February, gives major credit for the discovery to two students in her laboratory who were convinced that the transfer--long thought impossible by several scientists--could be successfully accomplished.
Graduate student Julie Burke and an undergraduate David Schneider (now at the department of bacteriology at the University of Wisconsin-Madison) originated the idea for the transfer system. A patent for the use of this technology in antibiotic drug discovery was issued to the University of Georgia Research Foundation in November.
Support for the work came from the National Science Foundation, Phizer Pharmaceutical Company, a Genetics Training Grant from the National Institutes of Health and a Senior Graduate Research Award from the University of Georgia.
The idea of using transduction--moving DNA from one organism to another using viruses called phages as carriers--is not new. Numerous problems have made transduction impractical if not impossible in Streptomyces, however. Researchers have long desired such a system, since it would allow the design of stronger or different drugs to fight infection or cancer.
There are, in fact, hundreds of species of Streptomyces, and more than two dozen are currently being used to improve human and animal health. The drugs must be created directly from the soil-borne organisms, though, and it can be expensive and time-consuming. Worse, resistance to commonly used antibiotics is growing more pronounced every year. New strains of infections are routinely killing patients who might have survived only a few years ago.
“The need for new and improved antibiotics is becoming a major issue for human health care. There are many `orphan’ drugs out there waiting to be developed if only the organisms that produce them could be manipulated,” said Westpheling. “In addition, the ability to shuffle the genetic pathways for existing drugs may lead to the production of truly new types of compounds for which there is no resistance."
The crucial problem solved by Westpheling and her team was that while phage mediated DNA transfer occurs, it was not detected because the phages are extremely virulent and kill cells that receive DNA. The team found a way, however, to remove the phages’ lethal impact--called superinfection killing--and allow them to serve as DNA carriers without killing the cells they transfer DNA into.
The researchers used a strain called Streptomyces coelicolor, which is the most genetically well-characterized actinomycete, an extremely diverse group of filamentous prokaryotic organisms, that includes most of the major natural-product antibiotics. They are unique among bacteria in that they grow as a branching hyphae similar to fungi as they gather nutrients from the soil. S. coelicolor has attracted considerable interest as a model organism and serves as a guide for the study of strains that make important therapeutics.
The result is a new genetic “postal system” that will allow researchers to create novel chemical backbones that could change or improve the function of Streptomyces in fighting infection or cancer. That could be crucial, since soil-borne Streptomyces--which are used by virtually every major pharmaceutical company--aren’t evolving quickly enough to keep up with the resistance that diseases are achieving against pathogens.
In addition to the practical importance of drug development, the use of transduction in Streptomyces will make a huge impact on the study of the biology of these organisms. Generalized transduction is a major tool that scientists use to map and manipulate such highly developed model systems as E. coli.
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