Exploring a Novel Anti-Gonococcal Compound for Combating Drug-Resistant <i>Neisseria gonorrhoeae</i>

The Gram-negative bacterium Neisseria gonorrhoeae, the causative agent of gonorrhea, is a significant public health concern due to its rapid development of resistance to antibiotics, leading to limited treatment options and potentially untreatable infections. This pathogen primarily infects the urogenital tract, but it can also affect the rectum, throat, and eyes, resulting in severe complications such as pelvic inflammatory disease and infertility if untreated. The rise in antibiotic-resistant gonorrhea underscores the urgent need for new therapeutics. To address this, suitable strains of N. gonorrhoeae for in vivo study were constructed. N. gonorrhoeae FA1090 is used in the mouse model of gonococcal infection due to its streptomycin resistance, which allows colonization. However, it is unsuitable for testing novel agents against multidrug-resistant N. gonorrhoeae due to its antibiotic susceptibility. Therefore, streptomycin-resistant mutants of N. gonorrhoeae CDC-181 (azithromycin-resistant) and WHO-X (ceftriaxone-resistant) were developed to evaluate the activity of potential anti-N. gonorrhoeae compounds. These mutants, CDC-181-rpsLA128G and WHO-X-rpsLA128G, successfully colonized the genital tracts of mice, making them suitable models for testing new treatments. Additionally, using a drug repurposing strategy, we identified nitroxoline, an FDA-approved drug, as a promising anti-gonococcal agent. Nitroxoline showed strong activity against a range of multidrug-resistant N. gonorrhoeae strains, including ceftriaxone-resistant ones, with an MIC90 of 0.5 µg/mL. It eradicated N. gonorrhoeae within 12 hours and prevented the development of resistant mutants. Nitroxoline also effectively penetrated human cervical cells and eradicated intracellular N. gonorrhoeae while minimally affecting commensal vaginal flora. Its mechanism involves chelation with metal ions, particularly Fe3+ and Fe2+. In conclusion, the development of streptomycin-resistant N. gonorrhoeae mutants and the identification of nitroxoline as a potent anti-gonococcal agent represent significant progress in combating multidrug-resistant gonorrhea. These findings offer promising avenues for new anti-gonococcal treatments in an era of increasing antibiotic resistance.