title: Actinonin, a naturally occurring antibacterial agent, is a potent deformylase inhibitor.
abstract: Peptide deformylase (PDF) is essential in prokaryotes and absent in mammalian cells, thus making it an attractive target for the discovery of novel antibiotics. We have identified actinonin, a naturally occurring antibacterial agent, as a potent PDF inhibitor. The dissociation constant for this compound was 0.3 x 10(-)(9) M against Ni-PDF from Escherichia coli; the PDF from Staphylococcus aureus gave a similar value. Microbiological evaluation revealed that actinonin is a bacteriostatic agent with activity against Gram-positive and fastidious Gram-negative microorganisms. The PDF gene, def, was placed under control of P(BAD) in E. coli tolC, permitting regulation of PDF expression levels in the cell by varying the external arabinose concentration. The susceptibility of this strain to actinonin increases with decreased levels of PDF expression, indicating that actinonin inhibits bacterial growth by targeting this enzyme. Actinonin provides an excellent starting point from which to derive a more potent PDF inhibitor that has a broader spectrum of antibacterial activity.
authors.affiliation: Versicor, Inc., Fremont, California 94555, USA.
authors.forename: D Z
authors.initials: DZ
authors.lastname: Chen
authors.forename: D V
authors.initials: DV
authors.lastname: Patel
authors.forename: C J
authors.initials: CJ
authors.lastname: Hackbarth
authors.forename: W
authors.initials: W
authors.lastname: Wang
authors.forename: G
authors.initials: G
authors.lastname: Dreyer
authors.forename: D C
authors.initials: DC
authors.lastname: Young
authors.forename: P S
authors.initials: PS
authors.lastname: Margolis
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.forename: Z J
authors.initials: ZJ
authors.lastname: Ni
authors.forename: J
authors.initials: J
authors.lastname: Trias
authors.forename: R J
authors.initials: RJ
authors.lastname: White
authors.forename: Z
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D006877:Hydroxamic Acids / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008667:Metalloproteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D015032:Zinc / Q000737:chemistry
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D008667:Metalloproteins; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase; D015032:Zinc; C010531:actinonin