Blocking Enzyme’s Pinching Action Could Thwart Antibiotic Resistance

Human infections resistant to multiple antibiotics continue to rise, and the hunt is on for ways to stem that superbug tide. Chemists have now revealed the structure of an enzyme that helps antibiotic resistance genes hop to new bacterial hosts—one route to superbug status (Proc. Natl. Acad. Sci. USA, DOI: 10.1073/pnas.1219701110).

The team also reports molecules that block the enzyme’s activity. Though the molecules are far from being drugs, the authors say the strategy represents a new idea for fighting superbugs.

The long-term goal of the work is to develop a companion therapy to traditional antibiotics that keeps resistance in check, explains Matthew R. Redinbo, the University of North Carolina, Chapel Hill, researcher who led the team.

To pass on antibiotic-thwarting genes to a nearby microorganism, a bacterium needs an enzyme to cut one strand of its own DNA. Redinbo’s team crystallized a complex of DNA and this nicking enzyme, which they obtained from a dangerous strain of methicillin-resistant Staphylococcus aureus (MRSA)—the first human pathogen to also pick up resistance to antibiotic heavy hitter vancomycin. They noticed two protein loops holding the DNA, “pinching it like a finger and thumb,” Redinbo says, arranging it for nicking. The nicked DNA strand peels off, so the bacterium can squirt it into its neighbors.

Eliminating those loops from the enzyme makes Staphylococcus far less able to share DNA, collaborator Neville Firth at the University of Sydney learned. And molecules that interfere with the DNA-loop interaction, polyamides from Peter B. Dervan’s Caltech lab, block the purified enzyme’s activity.

“Disrupting protein-DNA interactions is not an easy task,” says Miquel Coll, who has determined similar enzyme structures at the Institute for Research in Biomedicine in Barcelona. He thinks the team made good use of their structural information to develop their inhibitors.

The polyamides probably aren’t selective enough to work in cells or animals, Redinbo cautions. In addition to making improvements on that front, his team wants more structures of the nicking enzyme, including one after nicking takes place. “We only have a snapshot of the beginning of the process,” he says.