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
Institute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Univ. Paris-Sud, Université Paris-Saclay, 91198 Gif-sur-Yvette cedex, France.
UMR8601, LCBPT, CNRS Université Paris Descartes, PRES Paris Cité, 45 rue des Sts Pères 75270 Paris Cedex 06, France.
Sci Rep. 2016 Oct 20;6:35429. doi: 10.1038/srep35429.
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.
肽脱甲酰基酶（PDF）被认为是开发抗生素的一个理想靶点。我们对来自病原体无乳链球菌的一种新型PDF进行了广泛表征，结果表明其性质与其他已知的PDF相似。无乳链球菌PDF可作为PDF原型，因为它能够与几乎任何抑制剂化合物一起获得完整的三维、生物物理和动力学数据集。利用这个单一参考系统进行构效关系分析，使我们能够揭示不同PDF抑制剂的独特结合模式以及氢键在增强配体与靶点相互作用中的关键作用。我们提出这种蛋白质是一种不可替代的工具，它能够轻松且相关地对系列进行精细比较，以设计、挑战和验证新型抑制剂系列。作为概念验证，我们在此报告了一种恶二唑系列有效特异性细菌PDF抑制剂的设计与合成，该抑制剂对一种耐多药临床分离株具有强效抗菌活性。
