Advanced development of a potent dual-targeting TriBE class lead candidate to treat highly drug resistant Neisseria gonorrhoeae

Summary Gonorrhea infections represent a significant clinical management issue, as the emergence and spread of antimicrobial resistance in Neisseria gonorrhoeae poses a substantial challenge to global public health. Strains expressing multidrug resistant (MDR) and extensively drug-resistant (XDR) phenotypes have rendered many first- and second-line therapies ineffective, highlighting an urgent need for new antimicrobial agents with a novel mechanism of action. The TriBE (tricyclic GyrB/ParE) pyrimidoindole small molecule inhibitors were developed as promising candidates to combat drug-resistant N. gonorrhoeae. Unlike current drugs or drug candidates in clinical development, these dual binding compounds selectively target with high affinity the ATP-binding regions of DNA gyrase (GyrB) and topoisomerase (ParE), which are independent of other known drug interaction sites. Lead candidate JSF-2414 displays potent in vitro activity against N. gonorrhoeae clinical isolates including known drug-resistant strains. A phosphate prodrug, JSF-2659, developed to facilitate oral dosing was shown to be highly efficacious in reducing microbial burdens 4-5 log orders to the limit of detection in animal models of N. gonorrhoeae vaginal infection when delivered orally or via an intramuscular route. Importantly, the dual binding properties of JSF-2414 imparts a high barrier to resistance development, and it is a poor substrate for multidrug efflux pumps, a common mechanism of resistance in Gram-negative bacteria. Potent in vitro and in vivo activity, along with promising initial safety and toxicity profiling suggested that this class is well suited for advanced optimization. Leveraging close collaborative efforts between the Perlin lab and Merck & Co, our proposal aims to optimize the TriBE inhibitor series, focusing on identifying a superior lead candidate characterized by enhanced stability and oral bioavailability without the need for a phosphate prodrug. This candidate will be positioned for further development as an investigational new drug (IND) with the potential to effectively combat drug-resistant N. gonorrhoeae, aligning closely with the Target Product Profile (TPP) outlined by the WHO. The proposed timeline aims to achieve significant milestones, including the identification of a preclinical development candidate by Year 3 and a fully optimized and de-risked candidate for IND submission to the U.S. Food and Drug Administration (FDA) by the end of Year 5. In summary, the TriBE dual-targeting pyrimidoindole inhibitors represent a promising new weapon in combating antimicrobial resistance among N. gonorrhoeae, with the potential to deliver effective therapeutic solutions to mitigate the global health crisis associated with untreatable gonorrhea.