A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant Neisseria gonorrhoeae and Other High-Threat Pathogens

Antimicrob Agents Chemother. 2022 Sep 20;66(9):e0041422. doi: 10.1128/aac.00414-22. Epub 2022 Aug 16.


Drug-resistant Neisseria gonorrhoeae is a serious global health concern. New drugs are needed that can overcome existing drug resistance and limit the development of new resistances. Here, 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 was developed to target both ATP-binding regions of DNA gyrase (GyrB) and topoisomerase (ParE). JSF-2414 displays potent activity against N. gonorrhoeae, including drug-resistant strains. A phosphate pro-drug, 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 vancomycin-resistant Staphylococcus aureus (VRSA) and a model of Clostridioides difficile-induced colitis to be highly efficacious and protective. JSF-2659 is a novel preclinical drug candidate against high-threat multidrug resistant organisms with low potential to develop new resistance.

Keywords: C. difficile; Neisseria; Neisseria gonorrhoeae; VRSA; gyrase; topoisomerase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate
  • Animals
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • DNA Gyrase / genetics
  • Drug Resistance, Bacterial
  • Female
  • Gonorrhea* / drug therapy
  • Methanol / pharmacology
  • Methicillin-Resistant Staphylococcus aureus* / metabolism
  • Microbial Sensitivity Tests
  • Neisseria gonorrhoeae
  • Phosphates / pharmacology
  • Prodrugs* / pharmacology
  • Topoisomerase II Inhibitors / pharmacology


  • Anti-Bacterial Agents
  • Phosphates
  • Prodrugs
  • Topoisomerase II Inhibitors
  • Adenosine Triphosphate
  • DNA Gyrase
  • Methanol