title: Salicylidene Acylhydrazides and Hydroxyquinolines Act as Inhibitors of Type Three Secretion Systems in Pseudomonas aeruginosa by Distinct Mechanisms.
abstract: Type 3 secretion systems (T3SSs) are major virulence factors in Gram-negative bacteria.Pseudomonas aeruginosaexpresses two T3SSs, namely, an injectisome (iT3SS) translocating effector proteins in the host cell cytosol and a flagellum (fT3SS) ensuring bacterial motility. Inhibiting these systems is an appealing therapeutic strategy for acute infections. This study examines the protective effects of the salicylidene acylhydrazide INP0341 and of the hydroxyquinoline INP1750 (previously described as T3SS inhibitors in other species) toward cytotoxic effects ofP. aeruginosain vitroBoth compounds reduced cell necrosis and inflammasome activation induced by reference strains or clinical isolates expressing T3SS toxins or only the translocation apparatus. INP0341 inhibited iT3SS transcriptional activation, including in strains with constitutive iT3SS expression, and reduced the total expression of toxins, suggesting it targets iT3SS gene transcription. INP1750 inhibited toxin secretion and flagellar motility and impaired the activity of the YscN ATPase fromYersinia pseudotuberculosis(homologous to the ATPase present in the basal body ofP. aeruginosaiT3SS and fT3SS), suggesting that it rather targets a T3SS core constituent with high homology among iT3SS and fT3SS. This mode of action is similar to that previously described for INP1855, another hydroxyquinoline, againstP. aeruginosaThus, although acting by different mechanisms, INP0341 and INP1750 appear as useful inhibitors of the virulence ofP. aeruginosaHydroxyquinolines may have a broader spectrum of activity by the fact they act upon two virulence factors (iT3SS and fT3SS).
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Ahalieyah
authors.initials: A
authors.lastname: Anantharajah
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Julien M
authors.initials: JM
authors.lastname: Buyck
authors.affiliation: Creative Antibiotics, Umeå, Sweden.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Sundin
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Paul M
authors.identifier: 0000-0002-7121-3623
authors.initials: PM
authors.lastname: Tulkens
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
authors.affiliation: Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium francoise.vanbambeke@uclouvain.be.
authors.forename: Françoise
authors.identifier: 0000-0002-0052-7991
authors.initials: F
authors.lastname: Van Bambeke
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D006912:Hydroxyquinolines / Q000494:pharmacology*; D058847:Inflammasomes / Q000187:drug effects / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects*; D000069296:Type III Secretion Systems / Q000187:drug effects* / Q000378:metabolism; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D006834:Hydrazines; D006912:Hydroxyquinolines; C541377:INP 0341; D058847:Inflammasomes; D000069296:Type III Secretion Systems
keywords: NLRC4 inflammasome; Pseudomonas aeruginosa; flagella; inhibitors; type three secretion system; virulence