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 in vitro efficacy against enterococcal pathogens. However, only acetazolamide has been explored for in vivo 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 in vitro ADME profiles, and advanced a promising lead analog forward into in vivo 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 in vivo therapeutic potential for the treatment of septicemic vancomycin-resistant VRE infection.