TB Protein May Aid Drug Delivery

ATLANTA--A cell-piercing protein from the bacterium that causes tuberculosis (TB) could serve as a delivery system for future medicines. At the American Society for Microbiology's annual meeting here researchers reported yesterday that they had identified a short protein sequence that is key to the TB bacterium's ability to invade cells. Down the road, the protein may provide researchers with a powerful new tool to infuse cells with protein-based drugs and healthy genes for gene therapy.

Cells are normally very selective about what types of compounds they allow inside. While small molecules such as salt or carbohydrates readily pass through their membranes, larger molecules, such as proteins and nucleic acids, are blocked. Nevertheless, the TB bacterium and other cellular invaders manage to breach this barrier and force their way inside. Now researchers at the University of California at Berkeley have identified a TB protein called Mycobacterium Cell Entry Protein (MCEP), which pierces cells like a spear and allows TB to wedge through the membrane. The group, led by Lee Riley, then isolated what seems to be the spear's hardened point: A peptide containing just 22 of MCEP's 400 amino acids, which manages to worm its way into cells with nearly the same efficiency as the complete protein.

Next, the researchers tested whether their peptide--dubbed INV3--could shuttle other cargoes into cells. When they linked INV3 to a harmless, noninvasive strain of E. coli, they found that the bacteria were able to enter epithelial cells. They also linked it to b-galactosidase, a commonly used enzymatic marker that generates an intense blue color when it metabolizes the sugar galactose. When the enzyme was linked to the peptide, it could penetrate epithelial cells and turn them blue.

In an ironic twist, the new molecular shuttle may even prove useful in fighting TB, says Riley. The antibiotic amoxycillin is highly effective at killing TB in culture, but it doesn't work as well in the body, where the bacterium hides out inside cells. But amoxycillin microcapsules coated with INV3 or MCEP might penetrate infected cells, killing TB in its hiding place.

"This development sounds very interesting," says John Collier, a biomedical engineer at the Massachusetts Institute of Technology. "Breaching cell membranes with drugs has been an unsolved problem for 30 years. The question is can you get to the targeted cell without damaging other cells."

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