Enterococci carbonic anhydrase inhibition.

Carbonic anhydrase metalloenzymes are encoded in genomes throughout all kingdoms of life with a conserved function catalyzing the reversible conversion of CO to bicarbonate. Carbonic anhydrases have been well-investigated in humans, but are still relatively understudied in bacterial organisms, including Enterococci. Studies over the past decade have presented bacterial carbonic anhydrases as potential drug targets, with some chemical scaffolds potently inhibiting the Enterococcus carbonic anhydrases in vitro and displaying antimicrobial efficacy against Enterococcus organisms.

Neisseria gonorrhoeae carbonic anhydrase inhibition.

Carbonic anhydrases (CAs) are ubiquitous enzymes that are found in all kingdoms of life. Though different classes of CAs vary in their roles and structures, their primary function is to catalyze the reaction between carbon dioxide and water to produce bicarbonate and a proton. Neisseria gonorrhoeae encodes for three distinct CAs (NgCAs) from three different families: an α-, a β-, and a γ-isoform.

Optimization of Ethoxzolamide Analogs with Improved Pharmacokinetic Properties for Efficacy against .

Drug-resistant gonorrhea is caused by the bacterial pathogen , for which there is no recommended oral treatment. We have demonstrated that the FDA-approved human carbonic anhydrase inhibitor ethoxzolamide potently inhibits ; however, is not effective at reducing bioburden in a mouse model. Thus, we sought to optimize the pharmacokinetic properties of the ethoxzolamide scaffold.

Structural Characterization of Thiadiazolesulfonamide Inhibitors Bound to α-Carbonic Anhydrase.

Drug-resistant is a critical threat to public health, and bacterial carbonic anhydrases expressed by are potential new therapeutic targets to combat this pathogen. To further expand upon our recent reports of bacterial carbonic anhydrase inhibitors for the treatment of , our team has solved ligand-bound crystal structures of the FDA-approved carbonic anhydrase inhibitor acetazolamide, along with three analogs, in complex with the essential α-carbonic anhydrase isoform from . The structural data for the analogs presented bound to α-carbonic anhydrase supports the observed structure-activity relationship for inhibition with this scaffold against the enzyme.

Structure-Activity Relationship Studies of Acetazolamide-Based Carbonic Anhydrase Inhibitors with Activity against .

is an urgent threat to public health in the United States and around the world. Many of the current classes of antibiotics to treat infection are quickly becoming obsolete due to increased rates of resistance. Thus, there is a critical need for alternative antimicrobial targets and new chemical entities.