Investigating FDA-Approved Drugs for Treatment of Multidrug-Resistant Neisseria gonorrhoeae

Abstract

Neisseria gonorrhoeae, the causative agent of gonorrhea, is the second most prevalent sexually transmitted infection that leads to substantial morbidity and economic burden worldwide. Improperly treated or untreated gonorrhea can lead to severe and life-threatening complications, including abortion, infertility, pelvic pain, and maternal death. Neisseria gonorrhoeae has developed resistance to the formally and currently used antibiotics. The Centers for Disease Control and Prevention (CDC) have listed multi-drug resistant N. gonorrhoeae as an urgent threat that promptly requires the development of novel therapeutic agents. Traditional drug discovery and development is a time-consuming and costly process associated with high risks. To address the dire need to replenish the dry pipeline of anti-gonorrhea medications, drug repurposing is a promising approach. In this study, an FDA-approved drug library was screened, and 14 drugs were found to exhibit promising anti-gonococcal activity. Interestingly, three extremely potent and narrow-spectrum novel candidates, itraconazole, isavuconazole, and ravuconazole, are azole antifungals, and their activities were further investigated in vitro. Of the three azoles, ravuconazole displayed the most potent activity against N. gonorrhoeae clinical isolates. The time-kill assay revealed that the three azoles showed bactericidal activity. All three azole drugs showed a low frequency of resistance. Besides, isavuconazole and ravuconazole have a longer post-antibiotic effect than azithromycin. All three azoles cleared the burden of intracellular N. gonorrhoeae completely, which is superior to ceftriaxone. In conclusion, itraconazole, isavuconazole, and ravuconazole merit future investigation for the development of anti-gonorrheal therapeutics. This study provided unexplored avenues and promising opportunities that can be further evaluated to combat N. gonorrhoeae infection.