title: Synthesis and antibacterial activity of peptide deformylase inhibitors.
abstract: Peptide deformylase catalyzes the removal of the N-terminal formyl group from newly synthesized polypeptides in eubacteria. Its essential character in bacterial cells makes it an attractive target for antibacterial drug design. In this work, we have rationally designed and synthesized a series of peptide thiols that act as potent, reversible inhibitors of purified recombinant peptide deformylase from Escherichia coli and Bacillus subtilis. The most 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 microM ( approximately 2 microg/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 faecalis, 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 correlation between the MIC values and the K(I) values. These results suggest that peptide deformylase is the likely molecular target responsible for the antibacterial activity of these inhibitors and is therefore a viable target for antibacterial drug design.
authors.affiliation: Department of Chemistry and Ohio State Biochemistry Program, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Huntington
authors.forename: T
authors.initials: T
authors.lastname: Yi
authors.forename: Y
authors.initials: Y
authors.lastname: Wei
authors.forename: D
authors.initials: D
authors.lastname: Pei
mesh_terms: D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D001433:Bacteriolysis / Q000187:drug effects; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004352:Drug Resistance, Microbial; D013293:Enterococcus faecalis / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006860:Hydrogen Bonding; D008826:Microbial Sensitivity Tests; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D013212:Staphylococcus epidermidis / Q000166:cytology / Q000187:drug effects; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D004791:Enzyme Inhibitors; D010455:Peptides; D011994:Recombinant Proteins; D013438:Sulfhydryl Compounds; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase