In Vitro and In Vivo Activities of TP0480066, a Novel Topoisomerase Inhibitor, against Neisseria gonorrhoeae

Gonorrhea is a common, sexually transmitted disease caused by Neisseria gonorrhoeae Multidrug-resistant N. gonorrhoeae is an urgent threat, and the development of a new antimicrobial agent that functions via a new mechanism is strongly desired. We evaluated the in vitro and in vivo activities of a DNA gyrase/Topoisomerase IV inhibitor, TP0480066, which is a novel 8-(methylamino)-2-oxo-1,2-dihydroquinoline derivative. The MICs of TP0480066 were substantially lower than those of other currently or previously used antimicrobials against gonococcal strains demonstrating resistance to fluoroquinolones, macrolides, β-lactams, and aminoglycosides (MICs, ≤0.0005 μg/ml). Additionally, no cross-resistance was observed between TP0480066 and ciprofloxacin. The frequencies of spontaneous resistance to TP0480066 for N. gonorrhoeae ATCC 49226 were below the detection limit (<2.4 × 10^-10) at concentrations equivalent to 32× MIC. TP0480066 also showed potent in vitro bactericidal activity and in vivo efficacy in a mouse model of N. gonorrhoeae Infection. These data suggest that TP0480066 is a candidate antimicrobial agent for gonococcal infections.