A Novel Oral GyrB/ParE Dual Binding Inhibitor Effective against Multidrug-Resistant Neisseria gonorrhoeae and Other High-Threat Pathogens.
Steven ParkRiccardo RussoLandon WestfallRiju ShresthaMatthew ZimmermanVeronique Anne DartoisNatalia KurepinaBarry KreiswirthEric SingletonShao-Gang LiNisha MittalYong-Mo AhnJoseph BilottaKristie L ConnollyAnn E JerseJoel S FreundlichDavid S PerlinPublished in: Antimicrobial agents and chemotherapy (2022)
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.
Keyphrases
- multidrug resistant
- drug resistant
- gram negative
- acinetobacter baumannii
- klebsiella pneumoniae
- small molecule
- global health
- staphylococcus aureus
- escherichia coli
- anti inflammatory
- microbial community
- dna binding
- public health
- methicillin resistant staphylococcus aureus
- clostridium difficile
- drug induced
- single molecule
- binding protein
- quantum dots
- emergency department
- biofilm formation
- stem cells
- protein protein
- adverse drug
- mesenchymal stem cells
- cell therapy
- pseudomonas aeruginosa
- pet ct
- nucleic acid
- risk assessment
- electronic health record