Optimization of Ethoxzolamide Analogs with Improved Pharmacokinetic Properties for In Vivo Efficacy against Neisseria gonorrhoeae .

Drug-resistant gonorrhea is caused by the bacterial pathogen Neisseria gonorrhoeae , for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits N. gonorrhoeae ; however, is not effective at reducing N. gonorrhoeae bioburden in a mouse model. Thus, we sought to optimize the pharmacokinetic properties of the ethoxzolamide scaffold. These efforts resulted in analogs with improved activity against N. gonorrhoeae , increased metabolic stability in mouse liver microsomes, and improved Caco-2 permeability compared to ethoxzolamide. Improvement in these properties resulted in increased plasma exposure in vivo after oral dosing. Top compounds were investigated for in vivo efficacy in a vaginal mouse model of gonococcal genital tract infection, and they significantly decreased the gonococcal burden compared to vehicle and ethoxzolamide controls. Altogether, results from this study provide evidence that ethoxzolamide-based compounds have the potential to be effective oral therapeutics against gonococcal infection.