Identification of the cannabinoid receptor 1 antagonist, ibipinabant, as a potent inhibitor of Neisseria gonorrhoeae

Neisseria gonorrhoeae, the causative agent of the second-most prevalent sexually transmitted Bacterial disease globally, has been classified as an urgent threat to public health and a high-priority pathogen. Concerningly, N. gonorrhoeae has developed resistance to nearly all FDA-approved drugs. Currently, no approved oral therapies exist, with parenteral administration of ceftriaxone as the only available FDA-approved treatment option for multidrug-resistant gonococcal infections. Yet, ceftriaxone-resistant isolates have now been identified globally, further highlighting the urgent need for the development of novel Antibacterial agents. In a screen of 2,528 small molecules targeting G-protein-coupled receptors and related signaling pathways, ibipinabant, a potent Cannabinoid Receptor 1 antagonist, was identified as having the most potent anti-gonococcal activity. Ibipinabant demonstrated potent activity against a panel of 20 N. gonorrhoeae isolates, without inhibiting some representative Lactobacillus species of the vaginal microbiome. A time-kill assay revealed that ibipinabant is bactericidal, clearing the burden of N. gonorrhoeae (below the limit of detection) within 12 h. Ibipinabant was also able to clear the intracellular burden of N. gonorrhoeae inside human endocervical cells more effectively than the drug of choice, ceftriaxone. This drug was non-toxic against multiple cell lines and did not induce hemolysis of human red blood cells. Finally, in the in vivo mouse model of N. gonorrhoeae genital tract Infection, ibipinabant showed a significant reduction (>95%) in the gonococcal burden after 2 days of treatment. Altogether, these results indicate that ibipinabant is a promising candidate for drug repurposing as a novel antimicrobial against multidrug-resistant N. gonorrhoeae.