Structure-based design of a macrocyclic inhibitor for peptide deformylase

A macrocyclic, peptidomimetic inhibitor of peptide deformylase was designed by covalently cross-linking the P1' and PT side chains. The macrocycle, which contains an N-formylhydroxylamine side chain as the metal-chelating group, was synthesized from a diene precursor via olefin metathesis using Grubbs's catalyst. The cyclic inhibitor showed potent inhibitory activity toward Escherichia coli deformylase (K-I = 0.67 nM) and antibacterial activity against both Grampositive and Gram-negative bacteria (MIC = 0.7-12 mug/mL).