A unique peptide deformylase platform to rationally design and challenge novel active compounds

Sonia Fieulaine (1, 2) , Rodolphe Alves de Sousa (3) , Laure Maigre (4) , Karim Hamiche (2) , Mickael Alimi (3) , Jean-Michel Bolla (4) , Abbass Taleb (3) , Alexis Denis (5) , Jean-Marie Pagès (4) , Isabelle Artaud (3) , Thierry Meinnel (6) , Carmela Giglione (6)

1 IMAPP - Interactions et mécanismes d’assemblage des protéines et des peptides
2 I2BC - Institut de Biologie Intégrative de la Cellule
3 LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
4 TMCD2 - Transporteurs membranaires, chimioresistance et drug-design
5 GlaxoSmithKline
6 PROMTI - Maturation des proteines, destinée cellulaire et thérapeutique

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.

Domaines: Sciences du Vivant [q-bio]

Sonia Fieulaine, Rodolphe Alves de Sousa, Laure Maigre, Karim Hamiche, Mickael Alimi, et al.. A unique peptide deformylase platform to rationally design and challenge novel active compounds. Scientific Reports, 2016, 6, ⟨10.1038/srep35429⟩. ⟨hal-01412212⟩