Identification of the cannabinoid receptor 1 antagonist, ibipinabant, as a potent inhibitor of <i>Neisseria gonorrhoeae</i>

<i>Neisseria gonorrhoeae,</i> 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, <i>N. gonorrhoeae</i> 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 <i>N</i>. <i>gonorrhoeae</i> isolates, without inhibiting some representative <i>Lactobacillus</i> species of the vaginal microbiome. A time-kill assay revealed that ibipinabant is bactericidal, clearing the burden of <i>N. gonorrhoeae</i> (below the limit of detection) within 12 h. Ibipinabant was also able to clear the intracellular burden of <i>N. gonorrhoeae</i> 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 <i>in vivo</i> mouse model of <i>N. gonorrhoeae</i> 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 <i>N. gonorrhoeae</i>.