Repurposing epetraborole to combat <i>Neisseria gonorrhoeae</i> and <i>Chlamydia trachomatis</i> infections

<i>Neisseria gonorrhoeae</i> and <i>Chlamydia trachomatis</i> are the most common bacterial sexually transmitted infections. The World Health Organization (WHO) estimates that there were approximately 211 million cases of <i>chlamydia</i> and <i>gonorrhea</i> 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 <i>C. trachomatis</i>. Azithromycin (AZM) or doxycycline (DOX) is recommended for <i>C. trachomatis</i> infections; however, <i>N. gonorrhoeae</i> 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 <i>N. gonorrhoeae</i> and <i>C. trachomatis</i>. 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 <i>N. gonorrhoeae</i> with MIC ranging from 0.125 to 0.25 µg/mL. Additionally, EBO exhibited anti-<i>C</i>. <i>trachomatis</i> activity at concentrations of ≤1 µg/mL. Furthermore, EBO was capable of eliminating the intracellular burden of both <i>N. gonorrhoeae</i> and <i>C. trachomatis,</i> surpassing the activity of CRO and AZM. Moreover, unlike CRO and AZM, EBO showed limited activity against the normal vaginal microbiota. Finally, in an <i>in vivo</i> mouse model of CRO-resistant <i>N. gonorrhoeae</i> 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.