Abstract
gamma-Class carbonic anhydrases (CAs; EC 4.2.1.1) lack of extended inhibition characterization in comparison to alpha- and beta-class isozymes. For this reason, a panel of 22 phenols was investigated here for the inhibition of the gamma-CAs from the pathogenic bacteria Burkholderia pseudomallei (BpsCA gamma), Porphyromonas gingivalis (PgiCA), Vibrio cholerae (VchCA gamma) and from the antarctic bacteria Pseudoalteromonas haloplanktis (PhaCA gamma) and Colwellia psychrerythraea (CpsCA gamma). The exploration of the chemical space around the main phenolic group led to the discovery of a number of such derivatives showing effective, sometimes sub-micromolar inhibition against BpsCA gamma (K(I)s 0.45-8.6 mu M), PgiCA (K(I)s 0.36-9.8 mu M) and VchCA gamma (K(I)s 0.47-9.6 mu M). A subset of compounds even demonstrated a significant selectivity for the target gamma-CAs over the human physiologically most relevant isoform CA II. This study enriches the inhibitory profiles database for gamma-class CAs and promotes the identification of new potent and selective inhibitors against bacterial isoforms over human off-target ones. These agents are of remarkable interest and importance in the search of novel, worldwide required, antibiotic agents possessing alternative mechanisms of action as a strategy to overcome the spread to antimicrobic resistance.