Boularot Adrien, Giglione Carmela, Petit Sylvain, Duroc Yann, Alves de Sousa Rodolphe, Larue Valéry, Cresteil Thierry, Dardel Frédéric, Artaud Isabelle, Meinnel Thierry
UPR2355, Centre National de la Recherche Scientifique, Bâtiment 23, 1 Avenue de la Terrasse, F-91198 Gif-Sur-Yvette Cedex, France.
J Med Chem. 2007 Jan 11;50(1):10-20. doi: 10.1021/jm060910c.
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.
迫切需要新型抗生素来应对日益增加的病原体耐药性。肽脱甲酰基酶（PDF）最初被选定为特定的细菌靶点，但最近发现了一种人类同源物，抑制该同源物会导致细胞死亡。我们开发了一种双重筛选策略，以选择对人类PDF抑制作用低但高效的化合物。我们在体外选择了一种新的支架，它能够区分人类和细菌的PDF。构效关系分析确定了有效的抗生素，如2-（5-溴-1H-吲哚-3-基）-N-羟基乙酰胺（6b），其在体内的作用模式与先前鉴定的PDF抑制剂相同，但在人类细胞中没有这些抑制剂的凋亡效应。
