Repurposing epetraborole to combat Neisseria gonorrhoeae and Chlamydia trachomatis infections

Neisseria gonorrhoeae and Chlamydia trachomatis are the most common bacterial sexually transmitted infections. The World Health Organization (WHO) estimates that there were approximately 211 million cases of chlamydia and gonorrhea in 2020. Currently, no single drug is effective against both pathogens. Ceftriaxone (CRO) is the only recommended treatment for gonococcal infections but has no activity against C. trachomatis. Azithromycin (AZM) or doxycycline (DOX) is recommended for C. trachomatis infections; however, N. gonorrhoeae has developed resistance to both agents. Without new therapeutic options, these infections risk becoming untreatable. Utilizing a drug repurposing approach, we identified epetraborole (EBO) as a potent inhibitor for N. gonorrhoeae and C. trachomatis. EBO is a boron-containing compound currently in clinical trials for the treatment of non-tuberculous mycobacterial infections. EBO demonstrated potent activity against multidrug-resistant N. gonorrhoeae with MIC ranging from 0.125 to 0.25 µg/mL. Additionally, EBO exhibited anti-C. trachomatis activity at concentrations of ≤1 µg/mL. Furthermore, EBO was capable of eliminating the intracellular burden of both N. gonorrhoeae and C. trachomatis, surpassing the activity of CRO and AZM. Moreover, unlike CRO and AZM, EBO showed limited activity against the normal vaginal microbiota. Finally, in an in vivo mouse model of CRO-resistant N. gonorrhoeae genital tract infection, EBO exhibited a 99.95% reduction in bacterial burden after 2 days of treatment. Collectively, our findings highlight EBO as a promising candidate for the treatment of sexually transmitted infections that warrants further investigation.