LAUSR

Gepotidacin is a first-in-class triazaacenaphthylene antibacterial agent that selectively inhibits bacterial DNA gyrase and topoisomerase IV through a unique binding mode and has the potential to treat a number of bacterial diseases. Development of this new agent to treat pneumonic plague caused by Yersinia pestis depends on the U.S. Food and Drug Administration Animal Rule testing pathway, as testing in humans is not feasible. Here, preclinical studies were conducted in the African green monkey (AGM) inhalational model of pneumonic plague to test the efficacy of gepotidacin. AGMs infected with Y. pestis were dosed intravenously with gepotidacin (48, 36, or 28 milligrams/kilogram per day) for 10 days to provide a plasma concentration that would support a rationale for a 1000 mg twice or thrice daily intravenous dose in humans or saline as a control. The primary end point was AGM survival with predefined euthanasia criteria. Secondary end points included survival duration and bacterial clearance. Gepotidacin showed activity in vitro against diverse Y. pestis isolates including antibiotic-resistant strains. All control animals in the inhalational plague studies succumbed to plague and were blood culture and organ culture positive for Y. pestis. Gepotidacin provided a 75 to 100% survival benefit with all dose regimens. All surviving animals were blood culture and organ culture negative for Y. pestis. Our randomized, controlled efficacy trials in the AGM pneumonic plague nonhuman primate model together with the in vitro Y. pestis susceptibility data support the use of gepotidacin as a treatment for pneumonic plague caused by Y. pestis. Description Gepotidacin, a first-in-class triazaacenaphthylene antibacterial agent, shows efficacy in nonhuman primates for treating pneumonic plague. A new antibiotic for treating pneumonic plague Mortality rates from infection with Yersinia pestis are nearly 100% without treatment. Jakielaszek et al. now show that the triazaacenaphthylene antibacterial compound gepotidacin is active against a variety of Y. pestis strains in vitro, including strains resistant to other antibacterial agents. The authors demonstrate that gepotidacin is efficacious in a well-characterized, inhalational model of pneumonic plague in nonhuman primates at gepotidacin exposures that have been achieved in humans.