Author:
Fieulaine Sonia,Alves de Sousa Rodolphe,Maigre Laure,Hamiche Karim,Alimi Mickael,Bolla Jean-Michel,Taleb Abbass,Denis Alexis,Pagès Jean-Marie,Artaud Isabelle,Meinnel Thierry,Giglione Carmela
Abstract
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.
Publisher
Springer Science and Business Media LLC
Cited by
26 articles.
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