Hybrids of acylated homoserine lactone and nitric oxide donors as inhibitors of quorum sensing and virulence factors in Pseudomonas aeruginosa

2015 ◽  
Vol 13 (38) ◽  
pp. 9850-9861 ◽  
Author(s):  
Samuel K. Kutty ◽  
Nicolas Barraud ◽  
Kitty K. K. Ho ◽  
George M. Iskander ◽  
Renate Griffith ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Homoserine Lactone ◽  
Nitric Oxide Donors ◽  
Quorum Sensing Inhibition ◽  
Homoserine Lactones ◽  
Nitric Oxide Release ◽  
Acylated Homoserine Lactones

This paper discusses conversion of agonist acylated homoserine lactones (AHL) to antagonist AHLs with dual properties of quorum sensing inhibition and nitric oxide release.

scholarly journals Caenorhabditis elegans Senses Bacterial Autoinducers

2006 ◽  
Vol 72 (7) ◽  
pp. 5135-5137 ◽  
Author(s):  
Elmus Beale ◽  
Guigen Li ◽  
Man-Wah Tan ◽  
Kendra P. Rumbaugh
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Caenorhabditis Elegans ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Homoserine Lactones ◽  
C Elegans ◽  
Acylated Homoserine Lactones

ABSTRACT Pseudomonas aeruginosa uses virulence factors controlled by quorum sensing (QS) to kill Caenorhabditis elegans. Here we show that C. elegans is attracted to the acylated homoserine lactones (AHSLs) that mediate QS in P. aeruginosa. Our data also indicate that C. elegans can distinguish AHSLs and may use them to mediate aversive or attractive learning.

scholarly journals Revisiting the quorum-sensing hierarchy in Pseudomonas aeruginosa: the transcriptional regulator RhlR regulates LasR-specific factors

Microbiology ◽  
2009 ◽  
Vol 155 (3) ◽  
pp. 712-723 ◽  
Author(s):  
Valérie Dekimpe ◽  
Eric Déziel
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Transcriptional Regulator ◽  
Homoserine Lactone ◽  
The Other ◽  
Virulence Determinants ◽  
Late Stationary Phase ◽  
Regulatory Systems ◽  
Specific Factors

Pseudomonas aeruginosa uses the two major quorum-sensing (QS) regulatory systems las and rhl to modulate the expression of many of its virulence factors. The las system is considered to stand at the top of the QS hierarchy. However, some virulence factors such as pyocyanin have been reported to still be produced in lasR mutants under certain conditions. Interestingly, such mutants arise spontaneously under various conditions, including in the airways of cystic fibrosis patients. Using transcriptional lacZ reporters, LC/MS quantification and phenotypic assays, we have investigated the regulation of QS-controlled factors by the las system. Our results show that activity of the rhl system is only delayed in a lasR mutant, thus allowing the expression of multiple virulence determinants such as pyocyanin, rhamnolipids and C4-homoserine lactone (HSL) during the late stationary phase. Moreover, at this stage, RhlR is able to overcome the absence of the las system by activating specific LasR-controlled functions, including production of 3-oxo-C12-HSL and Pseudomonas quinolone signal (PQS). P. aeruginosa is thus able to circumvent the deficiency of one of its QS systems by allowing the other to take over. This work demonstrates that the QS hierarchy is more complex than the model simply presenting the las system above the rhl system.

scholarly journals Inhibition of Quorum Sensing in Pseudomonas aeruginosa by N-Acyl Cyclopentylamides

2007 ◽  
Vol 73 (10) ◽  
pp. 3183-3188 ◽  
Author(s):  
Takenori Ishida ◽  
Tsukasa Ikeda ◽  
Noboru Takiguchi ◽  
Akio Kuroda ◽  
Hisao Ohtake ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Biofilm Formation ◽  
Homoserine Lactone ◽  
Ring Structure ◽  
Response Regulators ◽  
Maximal Inhibition ◽  
Sensing Systems ◽  
Reporter Assays

ABSTRACT N-Octanoyl cyclopentylamide (C8-CPA) was found to moderately inhibit quorum sensing in Pseudomonas aeruginosa PAO1. To obtain more powerful inhibitors, a series of structural analogs of C8-CPA were synthesized and examined for their ability to inhibit quorum sensing in P. aeruginosa PAO1. The lasB-lacZ and rhlA-lacZ reporter assays revealed that the chain length and the ring structure were critical for C8-CPA analogs to inhibit quorum sensing. N-Decanoyl cyclopentylamide (C10-CPA) was found to be the strongest inhibitor, and its concentrations required for half-maximal inhibition for lasB-lacZ and rhlA-lacZ expression were 80 and 90 μM, respectively. C10-CPA also inhibited production of virulence factors, including elastase, pyocyanin, and rhamnolipid, and biofilm formation without affecting growth of P. aeruginosa PAO1. C10-CPA inhibited induction of both lasI-lacZ by N-(3-oxododecanoyl)-l-homoserine lactone (PAI1) and rhlA-lacZ by N-butanoyl-l-homoserine lactone (PAI2) in the lasI rhlI mutant of P. aeruginosa PAO1, indicating that C10-CPA interferes with the las and rhl quorum-sensing systems via inhibiting interaction between their response regulators (LasR and RhlR) and autoinducers.

scholarly journals Characterization of a Phosphotriesterase-Like Lactonase fromSulfolobus solfataricusand Its Immobilization for Disruption of Quorum Sensing

2010 ◽  
Vol 77 (4) ◽  
pp. 1181-1186 ◽  
Author(s):  
Filomena S. W. Ng ◽  
Daniel M. Wright ◽  
Stephen Y. K. Seah
Keyword(s):  
Quorum Sensing ◽  
Virulence Factors ◽  
Acyl Chain ◽  
Quorum Quenching ◽  
Homoserine Lactone ◽  
Homoserine Lactones ◽  
Specificity Constant ◽  
Chain Lengths ◽  
Quorum Sensing Signals

ABSTRACTSsoPox, a bifunctional enzyme with organophosphate hydrolase andN-acyl homoserine lactonase activities from the hyperthermophilic archaeonSulfolobus solfataricus, was overexpressed and purified from recombinantPseudomonas putidaKT2440 with a yield of 9.4 mg of protein per liter of culture. The enzyme has a preference forN-acyl homoserine lactones (AHLs) with acyl chain lengths of at least 8 carbon atoms, mainly due to lowerKmvalues for these substrates. The highest specificity constant obtained was forN-3-oxo-decanoyl homoserine lactone (kcat/Km= 5.5 × 103M−1·s−1), but SsoPox can also degradeN-butyryl homoserine lactone (C4-HSL) andN-oxo-dodecanoyl homoserine lactone (oxo-C12-HSL), which are important for quorum sensing in ourPseudomonas aeruginosamodel system. WhenP. aeruginosaPAO1 cultures were grown in the presence of SsoPox-immobilized membranes, the production of C4-HSL- and oxo-C12-HSL-regulated virulence factors, elastase, protease, and pyocyanin were significantly reduced. This is the first demonstration that immobilized quorum-quenching enzymes can be used to attenuate the production of virulence factors controlled by quorum-sensing signals.

scholarly journals The flavanone naringenin reduces the production of quorum sensing-controlled virulence factors in Pseudomonas aeruginosa PAO1

Microbiology ◽  
2011 ◽  
Vol 157 (7) ◽  
pp. 2120-2132 ◽  
Author(s):  
Olivier M. Vandeputte ◽  
Martin Kiendrebeogo ◽  
Tsiry Rasamiravaka ◽  
Caroline Stévigny ◽  
Pierre Duez ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Pathogenic Bacteria ◽  
Opportunistic Pathogen ◽  
Homoserine Lactone ◽  
Gene Products ◽  
Strain Pao1 ◽  
Preliminary Screening ◽  
Mutant Strains

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)-l-homoserine 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 (ΔlasI and ΔrhlI) 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.

scholarly journals Mouse and Human Cell Activation by N-Dodecanoyl-dl-Homoserine Lactone, a Chromobacterium violaceum Autoinducer

2006 ◽  
Vol 74 (12) ◽  
pp. 7029-7031 ◽  
Author(s):  
Kazunori Gomi ◽  
Toshiaki Kikuchi ◽  
Yutaka Tokue ◽  
Shigeru Fujimura ◽  
Akiko Uehara ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Inflammatory Cytokines ◽  
Human Cell ◽  
Cell Activation ◽  
Genetic Regulation ◽  
Homoserine Lactone ◽  
Chromobacterium Violaceum ◽  
Monocytic Cell ◽  
Homoserine Lactones

ABSTRACT Chromobacterium violaceum produces autoinducers, including homoserine lactones (HSLs), for genetic regulation. Among the seven HSLs derived from C. violaceum we evaluated, only C12-HSL stimulated the production of inflammatory cytokines in mammalian monocytic cell lines through the activation of the NF-κB signaling pathway besides their quorum-sensing role, like 3-oxo-C12-HSL from Pseudomonas aeruginosa.

scholarly journals The Pseudomonas aeruginosa Autoinducer N-3-Oxododecanoyl Homoserine Lactone Accelerates Apoptosis in Macrophages and Neutrophils

2003 ◽  
Vol 71 (10) ◽  
pp. 5785-5793 ◽  
Author(s):  
Kazuhiro Tateda ◽  
Yoshikazu Ishii ◽  
Manabu Horikawa ◽  
Tetsuya Matsumoto ◽  
Shinichi Miyairi ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Cell Lines ◽  
Virulence Factors ◽  
Homoserine Lactone ◽  
Significant Loss ◽  
Host Immune System ◽  
Dependent Manner ◽  
Monocytic Cell ◽  
Morphological Alterations

ABSTRACT Quorum-sensing systems are critical regulators of the expression of virulence factors of various organisms, including Pseudomonas aeruginosa. Las and Rhl are two major quorum-sensing components, and they are regulated by their corresponding autoinducers, N-3-oxododecanoyl homoserine lactone (3-oxo-C12-HSL) and N-butyryl-l-homoserine lactone (C4-HSL). Recent progress has demonstrated the potential of quorum-sensing molecules, especially 3-oxo-C12-HSL, for modulation of the host immune system. Here we show the specific ability of 3-oxo-C12-HSL to induce apoptosis in certain types of cells. When bone marrow-derived macrophages were incubated with synthetic 3-oxo-C12-HSL, but when they were incubated not C4-HSL, significant loss of viability was observed in a concentration (12 to 50 μM)- and incubation time (1 to 24 h)-dependent manner. The cytotoxic activity of 3-oxo-C12-HSL was also observed in neutrophils and monocytic cell lines U-937 and P388D1 but not in epithelial cell lines CCL-185 and HEp-2. Cells treated with 3-oxo-C12-HSL revealed morphological alterations indicative of apoptosis. Acceleration of apoptosis in 3-oxo-C12-HSL-treated cells was confirmed by multiple criteria (caspases 3 and 8, histone-associated DNA fragments, phosphatidylserine expression). Structure-activity correlation experiments demonstrated that the fine structure of 3-oxo-C12-HSL, the HSL backbone, and side chain length are required for maximal activity. These data suggest that Pseudomonas 3-oxo-C12-HSL specifically promotes induction of apoptosis, which may be associated with 3-oxo-C12-HSL-induced cytotoxicity in macrophages and neutrophils. Our data suggest that the quorum-sensing molecule 3-oxo-C12-HSL has critical roles in the pathogenesis of P. aeruginosa infection, not only in the induction of bacterial virulence factors but also in the modulation of host responses.

scholarly journals Influence of the MexAB-OprM Multidrug Efflux System on Quorum Sensing in Pseudomonas aeruginosa

1998 ◽  
Vol 180 (20) ◽  
pp. 5443-5447 ◽  
Author(s):  
Kelly Evans ◽  
Luciano Passador ◽  
Ramakrishnan Srikumar ◽  
Eric Tsang ◽  
Jonathon Nezezon ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Virulence Genes ◽  
Homoserine Lactone ◽  
Multidrug Efflux ◽  
Efflux System ◽  
Acylated Homoserine Lactone ◽  
Pai 1 ◽  
Multidrug Efflux System

ABSTRACT Pseudomonas aeruginosa nalB mutants which hyperexpress the MexAB-OprM multidrug efflux system produce reduced levels of several extracellular virulence factors known to be regulated by quorum sensing. Such mutants also produce less acylated homoserine lactone autoinducer PAI-1, consistent with an observed reduction inlasI expression. These data suggest that PAI-1 is a substrate for MexAB-OprM, and its resulting exclusion from cells hyperexpressing MexAB-OprM limits PAI-1-dependent activation of lasI and the virulence genes.

scholarly journals Efficacy of Liposomal Bismuth-Ethanedithiol-Loaded Tobramycin after Intratracheal Administration in Rats with Pulmonary Pseudomonas aeruginosa Infection

2012 ◽  
Vol 57 (1) ◽  
pp. 569-578 ◽  
Author(s):  
Moayad Alhariri ◽  
Abdelwahab Omri
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Quorum Sensing ◽  
Virulence Factors ◽  
Homoserine Lactone ◽  
Protease Production ◽  
Signal Molecules ◽  
Acyl Homoserine Lactone ◽  
Signal Molecule ◽  
Intratracheal Administration ◽  
Content Type

ABSTRACTWe sought to investigate alterations in quorum-sensing signal moleculeN-acyl homoserine lactone secretion and in the release ofPseudomonas aeruginosavirulence factors, as well as thein vivoantimicrobial activity of bismuth-ethanedithiol incorporated into a liposome-loaded tobramycin formulation (LipoBiEDT-TOB) administered to rats chronically infected withP. aeruginosa. The quorum-sensing signal moleculeN-acyl homoserine lactone was monitored by using a biosensor organism.P. aeruginosavirulence factors were assessed spectrophotometrically. An agar beads model of chronicPseudomonaslung infection in rats was used to evaluate the efficacy of the liposomal formulation in the reduction of bacterial count. The levels of active tobramycin in the lungs and the kidneys were evaluated by microbiological assay. LipoBiEDT-TOB was effective in disrupting both quorum-sensing signal moleculesN-3-oxo-dodeccanoylhomoserine lactone andN-butanoylhomoserine lactone, as well as significantly (P< 0.05) reducing lipase, chitinase, and protease production. At 24 h after 3 treatments, the CFU counts in lungs of animals treated with LipoBiEDT-TOB were of 3 log10CFU/lung, comparated to 7.4 and 4.7 log10CFU/lung, respectively, in untreated lungs and in lungs treated with free antibiotic. The antibiotic concentration after the last dose of LipoBiEDT-TOB was 25.1 μg/lung, while no tobramycin was detected in the kidneys. As for the free antibiotic, we found 6.5 μg/kidney but could not detect any tobramycin in the lungs. Taken together, LipoBiEDT-TOB reduced the production of quorum-sensing molecules and virulence factors and could highly improve the management of chronic pulmonary infection in cystic fibrosis patients.

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