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A new antibiotic’s mechanism of action

Apr. 25, 2019, 11:30 AM

by Leigh MacMillan

The novel antibacterial drug gepotidacin is showing clinical promise for the treatment of skin infections and gonorrhea.

Gepotidacin was developed in response to the rising bacterial resistance to fluoroquinolone drugs such as ciprofloxacin. Like fluoroquinolones, gepotidacin acts on the bacterial enzymes gyrase and topoisomerase IV, but details of its interaction with these enzymes are unknown.

Neil Osheroff, PhD, and colleagues have now characterized the mechanism of action of gepotidacin against Staphylococcus aureus gyrase.

They found that gepotidacin is a potent inhibitor of the enzyme. Unlike fluoroquinolones, which induce double-stranded DNA breaks, gepotidacin induced only single-stranded breaks, even at high concentrations and extended times of exposure. Crystal structures of gepotidacin with gyrase and nicked or intact DNA revealed details of the compound’s interaction with the enzyme and DNA.

The findings, reported in ACS Infectious Diseases, provide important insights on a first-in-class antibacterial and will guide the development of additional compounds that overcome antibacterial resistance.

This research was supported by a Merit Review award from the U.S. Veterans Administration, and grants and fellowships from the National Institutes of Health (GM126363, GM007628), the PhRMA Foundation and the American Association of Pharmaceutical Scientists.

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