1. J Infect Dis. 2016 Oct 1;214(7):1105-16. doi: 10.1093/infdis/jiw295. Epub 2016
Jul 13.

Inhibition of the Injectisome and Flagellar Type III Secretion Systems by INP1855
Impairs Pseudomonas aeruginosa Pathogenicity and Inflammasome Activation.

Anantharajah A(1), Faure E(2), Buyck JM(1), Sundin C(3), Lindmark T(3), Mecsas
J(4), Yahr TL(5), Tulkens PM(1), Mingeot-Leclercq MP(1), Guery B(2), Van Bambeke 

Author information: 
(1)Pharmacologie cellulaire et moléculaire, Louvain Drug Research Institute,
Université catholique de Louvain, Brussels, Belgium. (2)EA7366, Host-Pathogen
Translational Research Group, Faculté de Médecine, Université Lille Nord de
France, Lille, France. (3)Creative Antibiotics, Umeå, Sweden. (4)Department of
Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, 
Massachusetts. (5)Department of Microbiology, University of Iowa, Iowa City.

With the rise of multidrug resistance, Pseudomonas aeruginosa infections require 
alternative therapeutics. The injectisome (iT3SS) and flagellar (fT3SS) type III 
secretion systems are 2 virulence factors associated with poor clinical outcomes.
iT3SS translocates toxins, rod, needle, or regulator proteins, and flagellin into
the host cell cytoplasm and causes cytotoxicity and NLRC4-dependent inflammasome 
activation, which induces interleukin 1β (IL-1β) release and reduces interleukin 
17 (IL-17) production and bacterial clearance. fT3SS ensures bacterial motility, 
attachment to the host cells, and triggers inflammation. INP1855 is an iT3SS
inhibitor identified by in vitro screening, using Yersinia pseudotuberculosis
Using a mouse model of P. aeruginosa pulmonary infection, we show that INP1855
improves survival after infection with an iT3SS-positive strain, reduces
bacterial pathogenicity and dissemination and IL-1β secretion, and increases
IL-17 secretion. INP1855 also modified the cytokine balance in mice infected with
an iT3SS-negative, fT3SS-positive strain. In vitro, INP1855 impaired iT3SS and
fT3SS functionality, as evidenced by a reduction in secretory activity and
flagellar motility and an increase in adenosine triphosphate levels. As a result,
INP1855 decreased cytotoxicity mediated by toxins and by inflammasome activation 
induced by both laboratory strains and clinical isolates. We conclude that
INP1855 acts by dual inhibition of iT3SS and fT3SS and represents a promising
therapeutic approach.

© The Author 2016. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail

DOI: 10.1093/infdis/jiw295 
PMID: 27412581  [PubMed - in process]