Discovery and refinement of a new structural class of potent peptide deformylase inhibitors.
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.
Boularot
Adrien
A
UPR2355, Centre National de la Recherche Scientifique, Bâtiment 23, 1 Avenue de la Terrasse, F-91198 Gif-Sur-Yvette Cedex, France.
Giglione
Carmela
C
Petit
Sylvain
S
Duroc
Yann
Y
Alves de Sousa
Rodolphe
R
Larue
Valéry
V
Cresteil
Thierry
T
Dardel
Frédéric
F
Artaud
Isabelle
I
Meinnel
Thierry
T
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
C517635:2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide; D000900:Anti-Bacterial Agents; D006877:Hydroxamic Acids; D007211:Indoles; D000581:Amidohydrolases; C084507:peptide deformylase