Quorum-sensing (QS) regulates the production of key virulence factors in Pseudomonas aeruginosa and other important pathogenic bacteria. In this report, extracts of leaves and bark of Combretum albiflorum (Tul.) Jongkind (Combretaceae) were found to quench the production of QS-dependent factors in P. aeruginosa PAO1. Chromatographic fractionation of the crude active extract generated several active fractions containing flavonoids, as shown by their typical spectral features. Purification and structural characterization of one of the active compounds led to the identification of the flavan-3-ol catechin [(2R,3S)-2-(3,4-dihydroxyphenyl)-3,4-dihydro-1(2H)-benzopyran-3,5,7-triol]. The identity of catechin as one of the active molecules was confirmed by comparing the high-pressure liquid chromatography profiles and the mass spectrometry spectra obtained for a catechin standard and for the active C. albiflorum fraction. Moreover, standard catechin had a significant negative effect on pyocyanin and elastase productions and biofilm formation, as well as on the expression of the QS-regulated genes lasB and rhlA and of the key QS regulatory genes lasI, lasR, rhlI, and rhlR. The use of RhlRand LasR-based biosensors indicated that catechin might interfere with the perception of the QS signal N-butanoyl-L-homoserine lactone by RhlR, thereby leading to a reduction of the production of QS factors. Hence, catechin, along with other flavonoids produced by higher plants, might constitute a first line of defense against pathogenic attacks by affecting QS mechanisms and thereby virulence factor production.Pseudomonas aeruginosa is a gram-negative bacterium infecting insects, plants, animals, and humans (65). As an opportunistic pathogen, P. aeruginosa is a major cause of nosocomial diseases and mortality in immunocompromised patients and particularly in patients with cystic fibrosis, diffused panbronchitis, and pulmonary deficiencies (21, 54). Successful infection of diverse hosts is due to the profusion and diversity of virulence factors secreted by P. aeruginosa such as proteases, exopolysaccharides and redox-active compounds, as well as to its capacity to form biofilms (9, 60, 62).Many pathogenic bacteria trigger the production of their virulence factors in a population density-dependent manner, a cell-to-cell communication mechanism known as quorum sensing (QS) (24). This mechanism enables bacteria to detect their population density through the production, release, and perception of small diffusible molecules called autoinducers and to coordinate gene expression accordingly (7,9,13,24,84). In P. aeruginosa, two QS systems (las and rhl) drive the production (by the synthetases LasI and RhlI) and the perception (by the transcription factors LasR and RhlR) of the acyl-homoserine lactones (AHL) N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL), respectively (9, 62). Once LasR interacts with 3-oxo-C12-HSL, it induces the las system (by increasing lasI expression) and triggers the p...
Preliminary screening of the Malagasy plant Combretum albiflorum for compounds attenuating the production of quorum sensing (QS)-controlled virulence factors in bacteria led to the identification of active fractions containing flavonoids. In the present study, several flavonoids belonging to the flavone, flavanone, flavonol and chalcone structural groups were screened for their capacity to reduce the production of QS-controlled factors in the opportunistic pathogen Pseudomonas aeruginosa (strain PAO1). Flavanones (i.e. naringenin, eriodictyol and taxifolin) significantly reduced the production of pyocyanin and elastase in P. aeruginosa without affecting bacterial growth. Consistently, naringenin and taxifolin reduced the expression of several QS-controlled genes (i.e. lasI, lasR, rhlI, rhlR, lasA, lasB, phzA1 and rhlA) in P. aeruginosa PAO1. Naringenin also dramatically reduced the production of the acylhomoserine lactones N-(3-oxododecanoyl)-Lhomoserine lactone (3-oxo-C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL), which is driven by the lasI and rhlI gene products, respectively. In addition, using mutant strains deficient for autoinduction (DlasI and DrhlI) and LasR-and RhlR-based biosensors, it was shown that QS inhibition by naringenin not only is the consequence of a reduced production of autoinduction compounds but also results from a defect in the proper functioning of the RlhR-C4-HSL complex. Widely distributed in the plant kingdom, flavonoids are known for their numerous and determinant roles in plant physiology, plant development and in the success of plant-rhizobia interactions, but, as shown here, some of them also have a role as inhibitors of the virulence of pathogenic bacteria by interfering with QS mechanisms. INTRODUCTIONIn many pathogenic bacteria the production of virulence factors is triggered in a population density-dependent manner through quorum sensing (QS), a cell-to-cell communication mechanism that enables bacteria to coordinate virulence factor production by means of the synthesis, release and perception of small diffusible molecules called autoinducers (Antunes et al., 2010;Bjarnsholt et al., 2010;Case et al., 2008;Ng & Bassler, 2009). For instance, in the plant and mammal opportunistic pathogen Pseudomonas aeruginosa, two main QS systems (lasI/R and rhlI/R), responsible for the synthesis and perception of the acylhomoserine lactones (AHLs) N-(3-oxododecanoyl)-L-homoserine lactone (3-oxo-C12-HSL) and N-butanoyl-L-homoserine lactone (C4-HSL), respectively , control the expression Abbreviations: AHL, acylhomoserine lactone; C4-HSL, N-butanoyl-Lhomoserine lactone; ESI-MS, electrospray ionization-MS; HHL, Nhexanoyl-L-homoserine lactone; 3-oxo-C12-HSL, N-(3-oxododecanoyl)-L-homoserine lactone; PI, propidium iodide; QS, quorum sensing.3These authors contributed equally to this work. of an arsenal of virulence factors. The transcription factors LasR and RhlR interact with and are activated by 3-oxo-C12-HSL and C4-HSL, respectively, triggering the production of biofilms, LasB elastase...
Kidney ischemia/reperfusion injury (I/R) is characterized by renal dysfunction and tubular damages resulting from an early activation of innate immunity. Recently, nicotine administration has been shown to be a powerful inhibitor of a variety of innate immune responses, including LPS-induced toxaemia. This cholinergic anti-inflammatory pathway acts via the α7 nicotinic acetylcholine receptor (α7nAChR). Herein, we tested the potential protective effect of nicotine administration in a mouse model of renal I/R injury induced by bilateral clamping of kidney arteries. Renal function, tubular damages and inflammatory response were compared between control animals and mice receiving nicotine at the time of ischemia. Nicotine pretreatment protected mice from renal dysfunction in a dose-dependent manner and through the α7nAChR, as attested by the absence of protection in α7nAChR-deficient mice. Additionally, nicotine significantly reduced tubular damages, prevented neutrophil infiltration and decreased productions of the CXC-chemokine KC, TNF-α and the proinflammatory high-mobility group box 1 protein. Reduced tubular damage in nicotine pre-treated mice was associated with a decrease in tubular cell apoptosis and proliferative response as attested by the reduction of caspase-3 and Ki67 positive cells, respectively. All together, these data highlight that nicotine exerts a protective anti-inflammatory effect during kidney I/R through the cholinergic α7nAChR pathway. In addition, this could provide an opportunity to overcome the effect of surgical cholinergic denervation during kidney transplantation.
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