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.