Inhaled Lactonase Reduces Pseudomonas aeruginosa Quorum Sensing and Mortality in Rat Pneumonia

Sami Hraiech (1, 2) , Julien Hiblot (2) , John Lafleur (3, 4) , Hubert Lepidi (2) , Laurent Papazian (2, 5) , Jean-Marc Rolain (2) , Didier Raoult (2) , Mikael Elias (6) , Mark W. Silby (3) , Janek Bzdrenga (2) , Fabienne Bregeon (2) , Eric Chabriere (2)

1 DRIS - Service de réanimation-Détresses Respiratoires et Infections Sévères [Hôpital Nord - APHM]
2 URMITE - Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes
3 Department of Biology
4 Department of Emergency Medicine
5 Service de Réanimation Médicale-Détresse Respiratoires et Infections Sévères
6 Weizmann Institute of Science [Rehovot, Israël]

Rationale: The effectiveness of antibiotic molecules in treating Pseudomonas aeruginosa pneumonia is reduced as a result of the dissemination of bacterial resistance. The existence of bacterial communication systems, such as quorum sensing, has provided new opportunities of treatment. Lactonases efficiently quench acyl-homoserine lactone-based bacterial quorum sensing, implicating these enzymes as potential new anti-Pseudomonas drugs that might be evaluated in pneumonia. Objectives: The aim of the present study was to evaluate the ability of a lactonase called SsoPox-I to reduce the mortality of a rat P. aeruginosa pneumonia. Methods: To assess SsoPox-I-mediated quorum quenching, we first measured the activity of the virulence gene lasB, the synthesis of pyocianin, the proteolytic activity of a bacterial suspension and the formation of biofilm of a PAO1 strain grown in the presence of lactonase. In an acute lethal model of P. aeruginosa pneumonia in rats, we evaluated the effects of an early or deferred intra-tracheal treatment with SsoPox-I on the mortality, lung bacterial count and lung damage. Measurements and Primary Results: SsoPox-I decreased PAO1 lasB virulence gene activity, pyocianin synthesis, proteolytic activity and biofilm formation. The early use of SsoPox-I reduced the mortality of rats with acute pneumonia from 75% to 20%. Histological lung damage was significantly reduced but the lung bacterial count was not modified by the treatment. A delayed treatment was associated with a non-significant reduction of mortality. Conclusion: These results demonstrate the protective effects of lactonase SsoPox-I in P. aeruginosa pneumonia and open the way for a future therapeutic use.

Keywords: VIRULENCE; INHIBITORS; EXPRESSION; MOLECULE; AUTOINDUCTION; BIOFILM FORMATION; ACINETOBACTER-BAUMANNII; ANTIBACTERIAL EFFICACY; MOUSE MODEL; INFECTION

Domains: Life Sciences [q-bio]; Human health and pathology

Sami Hraiech, Julien Hiblot, John Lafleur, Hubert Lepidi, Laurent Papazian, et al.. Inhaled Lactonase Reduces Pseudomonas aeruginosa Quorum Sensing and Mortality in Rat Pneumonia. PLoS ONE, 2014, 9 (e107125 ), ⟨10.1371/journal.pone.0107125⟩. ⟨hal-01243714⟩