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454, Washington University Collaborate On Bacterial Strain Typing for Later Dxs

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In a collaboration that aims to identify bacterial nucleic-acid markers of drug susceptibility, next-generation sequencing company 454 Life Sciences and the Washington University Genome Sequencing Center in St. Louis will sequence disease-causing pathogens beginning early next year.

One aim of the project is to rapidly determine which antibiotics would be best suited for the treatment of particular infections, Elaine Mardis, co-director of the Genome Sequencing Center and an associate professor of genetics at Washington University School of Medicine, told Pharmacogenomics Reporter this week. "Clinically, a lot of time gets wasted where you're treating with an antibiotic to which the infecting strain is already resistant."

Using two 454 Gene Sequencer 20s, the Genome Sequencing Center will sequence entire bacterial genomes, in addition to sequencing RNA species active in wound and stool samples. There is a "possibility" that intellectual property coming out of the collaboration will be licensed out to diagnostics companies and other interested players, but "it remains to be seen, in terms of what we actually find out," Mardis said.

"We did negotiate, in terms of what the rights would be to certain inventions, should they arise," said Chris McLeod, 454 CEO, this week. "We certainly feel that to the extent that we're creating intellectual property, we'll have the rights to that-if they create it, there are certain opportunities for us," but the company will be focusing on applications of its core system in this project, he said. The university purchased a second Gene Sequencer 20 to help the project along, he added.

The majority of funding will come from 454 in the form of reagents and materials, but the total cost of the project will not be known until Mardis and colleagues finish the research plan, she said. The bacterial sequencing will begin "right after the first of the year" and should last for about a year, Mardis said.

McLeod declined to estimate the cost of the project to the company, but noted that it would expend mostly internal resources, such as materials and labor. The collaboration benefits 454 by giving it a chance to develop different approaches for RNA sequencing on the platform.

The group has not yet decided which bacteria it will sequence, and it has not completed a research plan, Mardis said. But as a result of the St. Louis Children's Hospital's involvement, "a lot of these pathogens are ones that specifically affect children," she said. "Probably [they] will be more intestinal pathogens, as well as skin-borne pathogens."

Common childhood enteric bacterial infections can be caused by Escherichia coli, Clostridium difficile, and Salmonella species. The main bacterial culprits of many types of childhood skin infections are group A ß hemolytic Streptococcus pyogenes, Staphylococcus aureus, and Streptococcus pneumoniae. Enterococcus faecalis and Enterococcus faecium derive from the intestine, and can cause a number of different infections. Along with methicillin-resistant S. aureus, vancomycin-resistant Enterococci cause many dangerous nosocomial infections.

Aside from the Children's Hospital, Mardis declined to name other project collaborators. "Being one of the top medical schools in the country, we obviously have some really nice collaborators already lined up that are interested in strain-typing approaches for various pathogens," she said.

The research project seems likely to study the different bacterial strains' response to a large number of different drugs. "What we're going to do is survey the broad spectrum [of antibiotics], because most of these [pathogens] are broadly resistant-so we'll do everything from penicillin to vancomycin, basically," Mardis said.

It isn't known how many antibiotic-resistant strains each bacterial species under study has, said Mardis. "It remains to be seen-that's one of the most exciting aspects of this project-it kind of remains to be seen what we'll find," she said. "This technology completely enables that-you're talking about a week to turn around a bacterial genome."

The scientists are not going to be searching specifically for new genes that confer antibiotic resistance, but after studying a set of general antibiotic-resistance genes, the project will incorporate genes that are less well described, including genes specific to particular pathogens, said Mardis.

Diagnostics that eventually result from the project might ultimately involve SNP genotyping, but in the near term any new strain-typing tests will probably make use of multiplex PCR and sequencing, Mardis said.

— Chris Womack ([email protected])

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