Synthesis and antibacterial activity of peptide deformylase inhibitors

Peptide deformylase catalyzes the removal of the N-terminal formyl group fr om newly synthesized polypeptides in eubacteria. Its essential character in bacterial cells makes it an attractive target for antibacterial drug desig n. In this work, we have rationally designed and synthesized a series of pe ptide thiols that act as potent, reversible inhibitors of purified recombin ant peptide deformylase from Escherichia coli and Bacillus subtilis. The mo st potent inhibitor has a K-I value of 11 nM toward the B. subtilis enzyme. These inhibitors showed antibacterial activity against both Gram-positive and Gram-negative bacteria, with minimal inhibitory concentrations (MIC) as low as 5 mu M (similar to 2 mu g/mL). The PDF inhibitors induce bacterial cell lysis and are bactericidal toward all four bacterial strains that have been tested, B. subtilis, Staphylococcus epidermidis, Enterococcus faecali s, and E, coli. Resistance evaluation of one of the inhibitors (1b) against B. subtilis showed that no resistant clone could be found from >1 x 10(9) cells. Quantitative analysis using a set of inhibitors designed to possess varying potencies against the deformylase enzyme revealed a linear correlat ion between the MIC values and the Kr values. These results suggest that pe ptide deformylase is the likely molecular target responsible for the antiba cterial activity of these inhibitors and is therefore a viable target fur a ntibacterial drug design.