title: Discovery and refinement of a new structural class of potent peptide deformylase inhibitors.
abstract: New classes of antibiotics are urgently needed to counter increasing levels of pathogen resistance. Peptide deformylase (PDF) was originally selected as a specific bacterial target, but a human homologue, the inhibition of which causes cell death, was recently discovered. We developed a dual-screening strategy for selecting highly effective compounds with low inhibition effect against human PDF. We selected a new scaffold in vitro that discriminated between human and bacterial PDFs. Analyses of structure-activity relationships identified potent antibiotics such as 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide (6b) with the same mode of action in vivo as previously identified PDF inhibitors but without the apoptotic effects of these inhibitors in human cells.
authors.affiliation: UPR2355, Centre National de la Recherche Scientifique, Bâtiment 23, 1 Avenue de la Terrasse, F-91198 Gif-Sur-Yvette Cedex, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Boularot
authors.forename: Carmela
authors.initials: C
authors.lastname: Giglione
authors.forename: Sylvain
authors.initials: S
authors.lastname: Petit
authors.forename: Yann
authors.initials: Y
authors.lastname: Duroc
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Alves de Sousa
authors.forename: Valéry
authors.initials: V
authors.lastname: Larue
authors.forename: Thierry
authors.initials: T
authors.lastname: Cresteil
authors.forename: Frédéric
authors.initials: F
authors.lastname: Dardel
authors.forename: Isabelle
authors.initials: I
authors.lastname: Artaud
authors.forename: Thierry
authors.initials: T
authors.lastname: Meinnel
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001412:Bacillus subtilis / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D001411:Geobacillus stearothermophilus / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007624:KB Cells; D009682:Magnetic Resonance Spectroscopy; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013329:Structure-Activity Relationship
chemical_list: C517635:2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide; D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D007211:Indoles; D000581:Amidohydrolases; C084507:peptide deformylase