Tigecycline displays bactericidal activity against multidrug-resistant Neisseria gonorrhoeae and enhances clearance from a mouse infection model

Abstract Objectives The global emergence of ceftriaxone-resistant Neisseria gonorrhoeae threatens current first-line treatment and necessitates alternative therapeutic options. Tigecycline, a last-line glycylcycline antibiotic approved for complicated infections, was evaluated for repurposing against N. gonorrhoeae through in vitro and in vivo activity studies. Methods Antimicrobial susceptibility testing was performed for 616 clinical isolates (2011–2024) from Hangzhou, China, and bactericidal activity was determined in time-kill assays. A mouse vaginal tract infection model was used to evaluate in vivo tigecycline activity. Chequerboard assays were performed to assess interactions between tigecycline and ceftriaxone. Results Tigecycline demonstrated potent activity (MIC50: 0.125 mg/L; MIC90: 0.25 mg/L), including against tetracycline-resistant (tetracycline MIC50: 2 mg/L; MIC90: 64 mg/L) and high-level ceftriaxone-resistant (ceftriaxone MIC50: 0.03 mg/L; MIC90: 0.125 mg/L) strains. Time-kill assays (2 strains) revealed concentration-dependent bactericidal activity, with 4×MIC achieving ≥105-fold killing. In the mouse vaginal tract infection model, high-dose tigecycline (25 mg/kg) significantly enhanced bacterial clearance, eliminating infection within 3–6 days compared to 8–12 days in vehicle controls, and substantially reduced bacterial burden. Chequerboard assays against 21 isolates (10 ceftriaxone-susceptible, 11 ceftriaxone-resistant) demonstrated indifferent interactions between tigecycline and ceftriaxone (fractional inhibitory concentration indices 1.03–2.56), indicating no antagonism. Conclusions These findings establish that tigecycline exhibits potent, rapid bactericidal activity against N. gonorrhoeae, including against high-level ceftriaxone-resistant strains, with robust in vivo efficacy. They support further investigation of tigecycline as a potential repurposing candidate for multidrug-resistant gonorrhoea, although its clinical role remains to be defined.