Hit-to-Lead Optimization of Acetazolamide-Based Bacterial Carbonic Anhydrase Inhibitors with Efficacy In Vivo for Treatment of Vancomycin-Resistant Enterococci Septicemia

As one of the leading causes of hospital-acquired infections reported by the National Healthcare Safety Network, vancomycin-resistant enterococci (VRE) continue to afflict patients in healthcare facilities, with limited FDA-approved drugs available for treating systemic infections. Our group previously showed the 1,3,4-thiadiazole acetazolamide human carbonic anhydrase inhibitor scaffold can be repositioned with potent <i>in vitro</i> efficacy against enterococcal pathogens. However, only acetazolamide has been explored for <i>in vivo</i> efficacy in murine septicemia models. Herein, we report a hit-to-lead account in which we expand the structure-activity relationship for the 1,3,4-thiadiazole scaffold, identified lead candidates with favorable <i>in vitro</i> ADME profiles, and advanced a promising lead analog forward into <i>in vivo</i> pharmacokinetic studies. Ultimately, we demonstrated efficacy in a murine septicemic peritonitis infection model after oral dosing. Overall, we demonstrate a successful example of an acetazolamide-based lead compound with <i>in vivo</i> therapeutic potential for the treatment of septicemic vancomycin-resistant VRE infection.