Inhibitors of the Neisseria meningitidis PilF ATPase provoke type IV pilus disassembly
| Autor: | Cedric Couturier, Sylvie Goussard, Guillaume Duménil, Dorian Obino, Youxin Kong, Ximing Xu, Flore Aubey, Stéphane Renard, Catherine Lapeyrere, Judith Souphron, Jean-Philippe Corre |
|---|---|
| Přispěvatelé: | Pathogénèse des Infections vasculaires / Pathogenesis of Vascular Infections, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Sanofi Pasteur [Marcy-l'Étoile, France], This work was supported by a Recherches Partenariales et Innovation Biomédicale grant from the Agence Nationale pour la Recherche, the Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence, and by the vascular infections pathogenesis European Research Council consolidator grant. D.O. was supported by a Pasteur-Roux Postdoctoral Fellowship from the Institut Pasteur., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Obino, Dorian, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
MESH: High-Throughput Screening Assays
BIOLOGICAL SCIENCES ATPase Microbiology Type four pili Virulence Pilus retraction medicine.disease_cause Pilus MESH: Neisseria meningitidis Microbiology MESH: Fimbriae Bacterial 03 medical and health sciences Sepsis type IV pilus MESH: Anti-Bacterial Agents inhibitors Extracellular medicine MESH: Adenosine Triphosphatases Structure–activity relationship Meningitis Endothelium MESH: Bacterial Adhesion MESH: Human Umbilical Vein Endothelial Cells bacteria MESH: Bacterial Proteins 030304 developmental biology 0303 health sciences Multidisciplinary MESH: Humans biology 030306 microbiology Chemistry Neisseria meningitidis biology.organism_classification [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology virulence MESH: Enzyme Inhibitors biology.protein Adhesion [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology Neisseria Bacteria MESH: Cells Cultured |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2019, 116 (17), pp.8481-8486. ⟨10.1073/pnas.1817757116⟩ Proceedings of the National Academy of Sciences of the United States of America, 2019, 116 (17), pp.8481-8486. ⟨10.1073/pnas.1817757116⟩ |
| ISSN: | 0027-8424 1091-6490 |
| DOI: | 10.1073/pnas.1817757116⟩ |
| Popis: | International audience; Despite the availability of antibiotics and vaccines, Neisseria meningitidis remains a major cause of meningitis and sepsis in humans. Due to its extracellular lifestyle, bacterial adhesion to host cells constitutes an attractive therapeutic target. Here, we present a high-throughput microscopy-based approach that allowed the identification of compounds able to decrease type IV pilus-mediated interaction of bacteria with endothelial cells in the absence of bacterial or host cell toxicity. Compounds specifically inhibit the PilF ATPase enzymatic activity that powers type IV pilus extension but remain inefficient on the ATPase that promotes pilus retraction, thus leading to rapid pilus disappearance from the bacterial surface and loss of pili-mediated functions. Structure activity relationship of the most active compound identifies specific moieties required for the activity of this compound and highlights its specificity. This study therefore provides compounds targeting pilus biogenesis, thereby inhibiting bacterial adhesion, and paves the way for a novel therapeutic option for meningococcal infections. |
| Databáze: | OpenAIRE |
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