1. Antimicrob Agents Chemother. 2017 May 24;61(6). pii: e02566-16. doi:
10.1128/AAC.02566-16. Print 2017 Jun.

Salicylidene Acylhydrazides and Hydroxyquinolines Act as Inhibitors of Type Three
Secretion Systems in Pseudomonas aeruginosa by Distinct Mechanisms.

Anantharajah A(1), Buyck JM(1), Sundin C(2), Tulkens PM(1), Mingeot-Leclercq
MP(1), Van Bambeke F(3).

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium.
(2)Creative Antibiotics, Umeå, Sweden.
(3)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium

Type 3 secretion systems (T3SSs) are major virulence factors in Gram-negative
bacteria. Pseudomonas aeruginosa expresses 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 of P. aeruginosain vitro Both 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 from Yersinia
pseudotuberculosis (homologous to the ATPase present in the basal body of P.
aeruginosa iT3SS 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,
against P. aeruginosa Thus, although acting by different mechanisms, INP0341 and 
INP1750 appear as useful inhibitors of the virulence of P. aeruginosa
Hydroxyquinolines may have a broader spectrum of activity by the fact they act
upon two virulence factors (iT3SS and fT3SS).

Copyright © 2017 American Society for Microbiology.

DOI: 10.1128/AAC.02566-16 
PMID: 28396545