Antibiotic Bouncer

Contrary to previous assumptions that macrolide antibiotics completely block the exit tunnel of ribosomes, new evidence shows that some peptides are allowed to pass.

By | March 1, 2013

EDITOR'S CHOICE IN DRUG DISCOVERY

LEAKY PLUG: Binding of the antibiotic erythromycin (orange) during protein translation stops the ribosome (gray) from producing most proteins, except those with a particular N-terminal sequence.COURTESY OF ALEXANDER MANKIN

The paper
K. Kannan et al., “Selective protein synthesis by ribosomes with a drug-obstructed exit tunnel,” Cell, 151:508-20, 2012.

The finding
Macrolides are widely used antibiotics that are thought to act by binding to and plugging up the ribosome, thereby halting protein translation. But “several reports in the past didn’t fit too snugly in this model,” says Alexander Mankin of the University of Illinois at Chicago. He and his colleagues retested the assumption by treating E. coli with high doses of the macrolide erythromycin and found that some proteins were still translated.

The selectivity
Mankin’s group found that translation was not halted completely, but rather declined by about 94 percent, and that the successfully translated products were specific to several types of protein, including a number of membrane proteins and the histone-like protein H-NS.

The escape route
As H-NS is synthesized, its N terminus comes into contact with the antibiotic erythromycin. The researchers fused the N-terminal sequence of hns to another gene for a protein whose translation is normally blocked in the presence of the antibiotic. The new combo protein was able to successfully escape the ribosome, most likely by snaking around the antibiotic.

The utility
Mankin says this new perspective on macrolide antibiotics opens the door to using them as ribosomal modulators. “In our case the macrolide is essentially a small molecule, which binds in the exit tunnel of the ribosome and converts it into a selective protein-synthesizing machine,” he says. Axel Innis, a group leader at the European Institute for Chemistry and Biology in Bordeaux, France, who was not part of the study, says there are clinical implications too. “It changes our understanding of how these molecules work and how you could make new ones that would be more specific and more potent.”

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