title: A unique peptide deformylase platform to rationally design and challenge novel active compounds.
abstract: Peptide deformylase (PDF) is considered an excellent target to develop antibiotics. We have performed an extensive characterization of a new PDF from the pathogen Streptococcus agalactiae, showing properties similar to other known PDFs. S. agalactiae PDF could be used as PDF prototype as it allowed to get complete sets of 3-dimensional, biophysical and kinetic data with virtually any inhibitor compound. Structure-activity relationship analysis with this single reference system allowed us to reveal distinct binding modes for different PDF inhibitors and the key role of a hydrogen bond in potentiating the interaction between ligand and target. We propose this protein as an irreplaceable tool, allowing easy and relevant fine comparisons between series, to design, challenge and validate novel series of inhibitors. As proof-of-concept, we report here the design and synthesis of effective specific bacterial PDF inhibitors of an oxadiazole series with potent antimicrobial activity against a multidrug resistant clinical isolate.
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Fieulaine
authors.affiliation: UMR8601, LCBPT, CNRS Université Paris Descartes, PRES Paris Cité, 45 rue des Sts Pères 75270 Paris Cedex 06, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Alves de Sousa
authors.affiliation: UMR_MD1, Aix-Marseille Univ, IRBA, Facultés de Médecine et de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Maigre
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Hamiche
authors.affiliation: UMR8601, LCBPT, CNRS Université Paris Descartes, PRES Paris Cité, 45 rue des Sts Pères 75270 Paris Cedex 06, France.
authors.forename: Mickael
authors.initials: M
authors.lastname: Alimi
authors.affiliation: UMR_MD1, Aix-Marseille Univ, IRBA, Facultés de Médecine et de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Bolla
authors.affiliation: UMR8601, LCBPT, CNRS Université Paris Descartes, PRES Paris Cité, 45 rue des Sts Pères 75270 Paris Cedex 06, France.
authors.forename: Abbass
authors.initials: A
authors.lastname: Taleb
authors.affiliation: GlaxoSmithKline, ZA Courtaboeuf, 25 Avenue du Québec, 91140 Villebon-sur-Yvette, France.
authors.forename: Alexis
authors.initials: A
authors.lastname: Denis
authors.affiliation: UMR_MD1, Aix-Marseille Univ, IRBA, Facultés de Médecine et de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille Cedex 05, France.
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Pagès
authors.affiliation: UMR8601, LCBPT, CNRS Université Paris Descartes, PRES Paris Cité, 45 rue des Sts Pères 75270 Paris Cedex 06, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Artaud
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Meinnel
authors.affiliation: Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
authors.forename: Carmela
authors.initials: C
authors.lastname: Giglione