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April 14, 1997

Biochemists unveil the molecular dances of antibiotics and bacterial RNA

Scientists at UCSC have exposed the precise interactions between a common class of antibiotics and the vital machinery in bacteria that they disable, setting the stage for targeted efforts by researchers to design new and more effective drugs.

A team led by biochemist Joseph Puglisi solved the puzzle of how the antibiotics grab a bacterium's ribosomes--the factories in every cell that make the proteins an organism needs to survive. The answers, mapped out atom by painstaking atom, shed light on why the antibiotics kill bacteria but not people, as well as how bacteria manage an end run around the drugs by developing resistance to their crippling tactics.

Puglisi's group focused first on paromomycin, one of the naturally occurring antibiotics called "aminoglycosides." Doctors have used aminoglycosides for decades to treat bacterial infections, but they have become less effective as antibiotic resistance has spread. Further, the details of how aminoglycosides work in the cell were poorly understood. Researchers knew only that the drugs latched directly onto bacterial ribosomes and somehow disrupted their protein assembly lines.

The UCSC team solved the structure of the drug attached to a short bit of RNA from the most critical part of the bacterial ribosome. Other scientists had probed how antibiotics link to proteins, but none had deciphered an antibiotic-RNA complex.

"There's a big rebirth in the idea of targeting RNA in cells by using small molecules," Puglisi said. "This is an example of how these 'lock-and-key' systems work. Manipulating the details of this system suggests a strategy for a whole new field of RNA-drug interactions."

Puglisi's lab published its paromomycin research in the November 22 Science. At the ACS meeting, Puglisi also will report on the solutions of other aminoglycoside-RNA complexes.

In three dimensions, the structures reveal that the ribosome forms a small pocket into which the L-shaped antibiotic molecules fit precisely. Chemical groups at several spots interact to "glue" the two units together. The group's research exposes in detail where those atomic attachments occur.

This level of scrutiny has allowed Puglisi and his coworkers to address why the antibiotics act selectively on bacteria. A tiny evolutionary switch between a stretch of RNA in bacteria and in higher organisms, it turns out, is enough to disrupt the pocket into which the antibiotic molecule clicks. Thus, the fit isn't as tight in people as it is in bacteria.

However, resistance arises easily. A single change in either the RNA sequence of the bacterial ribosome or the structure of the antibiotic molecule can prevent them from fitting snugly. "Our research shows exactly which parts of the structure are important to the functions of these drugs," Puglisi said. "So, we can try to vary the other parts to come up with versions that are less toxic to humans and less prone to resistance."


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