Inhibition of bacterial peptide deformylase by biaryl acid analogs

Peptide deformylase is an essential eubacterial metalloenzyme involved in t he maturation of proteins by cleaving the N-formyl group from N-blocked met hionine polypeptides. Biaryl acid analogs containing tetrazole, acyl sulfon amide, or carboxylate pharmacophores were found to be potent inhibitors of recombinant Escherichia coli peptide deformylase. Two of these compounds, a biphenyl tetrazole, compound 1, and a biphenyl acyl sulfonamide, compound 4, were competitive inhibitors with Ki values of 1.2 and 6.0 mu M, respecti vely. By analogy to the binding of related compounds to other metalloenzyme s such as Bacteroides fragilis metallo-beta-lactamase CcrA and human carbon ic anhydrase, a mechanism of inhibition is proposed for these peptide defor mylase inhibitors where the acidic moieties form direct ionic interactions with the active site metal cation, (C) 2000 Academic Press.