A novel oral GyrB/ParE dual binding inhibitor effective against multidrug resistant Neisseria gonorrhoeae and other high-threat pathogens

Park, S.; Russo, R.; Westfall, L.; Shrestha, R.; Zimmerman, M.; Dartois, V. A.; Kurepina, N.; Kreiswith, B.; Singleton, E.; LI, S.-G.; Mittal, N.; Ahn, Y.-M.; Bilotta, j.; Connolly, K. L.; Jerse, A. E.; Freundlich, J. S.; Perlin, D. S.

doi:10.1101/2022.03.23.485573

bioRxiv · 10.1101/2022.03.23.485573

A novel oral GyrB/ParE dual binding inhibitor effective against multidrug resistant Neisseria gonorrhoeae and other high-threat pathogens

Park, S.·Russo, R.·Westfall, L.·Shrestha, R.·Zimmerman, M.·Dartois, V. A.·Kurepina, N.·Kreiswith, B.·Singleton, E.·LI, S.-G.·Mittal, N.·Ahn, Y.-M.·Bilotta, j.·Connolly, K. L.·Jerse, A. E.·Freundlich, J. S.·Perlin, D. S.

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Abstract

Drug resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance, as well as limit development of new resistance. We describe the small molecule tricyclic pyrimidoindole JSF-2414 [8-(6- fluoro-8-(methylamino)-2-((2-methylpyrimidin-5-yl)oxy)-9H-pyrimido[4,5-b]indol-4-yl)-2- oxa-8-azaspiro[4.5]decan-3-yl)methanol], which simultaneously binds to ATP binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae including drug-resistant strains. A phosphate prodrug JSF-2659 was developed to facilitate oral dosing. In two different animal models of Neisseria gonorrhoeae vaginal infection, JSF-2659 was highly efficacious in reducing microbial burdens to the limit of detection. The parent molecule also showed potent in vitro activity against high-threat Gram positive organisms, and JSF-2659 was shown in a deep tissue model of VRSA and a model of C. difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.

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Park, S., Russo, R., Westfall, L., Shrestha, R., Zimmerman, M., Dartois, V. A., Kurepina, N., Kreiswith, B., Singleton, E., LI, S.-G., Mittal, N., Ahn, Y.-M., Bilotta, j., Connolly, K. L., Jerse, A. E., Freundlich, J. S., Perlin, D. S.. 2022-03-24. A novel oral GyrB/ParE dual binding inhibitor effective against multidrug resistant Neisseria gonorrhoeae and other high-threat pathogens. https://doi.org/10.1101/2022.03.23.485573

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