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Dubern JF, Diggle SP.. Quorum sensing by 2-alkyl-4-quinolones in Pseudomonas aeruginosa and other bacterial species. Mol Biosyst 4: 882-888

Institute of Infection, Immunity & Inflammation, Centre of Biomolecular Sciences, University of Nottingham, Nottingham, United Kingdom.
Molecular BioSystems (Impact Factor: 3.21). 10/2008; 4(9):882-8. DOI: 10.1039/b803796p
Source: PubMed

ABSTRACT

Pseudomonas aeruginosa produces the cell-to-cell signal molecule 2-heptyl-3-hydroxy-4-quinolone (The Pseudomonas quinolone signal; PQS), which is integrated within a complicated quorum sensing signaling system. PQS belongs to the family of 2-alkyl-4-quinolones (AQs), which have been previously described for their antimicrobial activities. PQS is synthesized via the pqsABCDE operon which is responsible for generating multiple AQs including 2-heptyl-4-quinolone (HHQ), the immediate PQS precursor. In addition, PQS signaling plays an important role in P. aeruginosa pathogenesis because it regulates the production of diverse virulence factors including elastase, pyocyanin and LecA lectin in addition to affecting biofilm formation. Here, we summarize the most recent findings on the biosynthesis and regulation of PQS and other AQs including the discovery of AQs in other bacterial species.

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    • "The las and rhl systems use homoserine lactones as signal molecules (N-(3- oxo-dodecanoyl)-L-homoserine lactone and N-(butanoyl)-L-homoserine lactone, respectively) which are commonplace among Gramnegative bacteria [5]. The pqs system, on the other hand, is employed only by some Pseudomonas and Burkholderia species and operates via the autoinducers PQS (Pseudomonas Quinolone Signal; 2-heptyl-3-hydroxy-4(1H)-quinolone) and its precursor HHQ (2-heptyl-4(1H)-quinolone) [6]. PQS and HHQ interact with the transcriptional regulator PqsR (also called MvfR) controlling the production of virulence factors, such as pyocyanin, elastase and hydrogen cyanide [7], as well as the formation of biofilms [8]. "
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    ABSTRACT: A new strategy for treating Pseudomonas aeruginosa infections could be disrupting the Pseudomonas Quinolone Signal (PQS) quorum sensing (QS) system. The goal is to impair communication among the cells and, hence, reduce the expression of virulence factors and the formation of biofilms. PqsD is an essential enzyme for the synthesis of PQS and shares some features with chalcone synthase (CHS2), an enzyme expressed in Medicago sativa. Both proteins are quite similar concerning the size of the active site, the catalytic residues and the electrostatic surface potential at the entrance of the substrate tunnel. Hence, we evaluated selected substrates of the vegetable enzyme as potential inhibitors of the bacterial protein. This similarity-guided approach led to the identification of a new class of PqsD inhibitors having a catechol structure as an essential feature for activity, a saturated linker with two or more carbons and an ester moiety bearing bulky substituents. The developed compounds showed PqsD inhibition with IC50 values in the single-digit micromolar range. The binding mode of these compounds was investigated by Surface Plasmon Resonance (SPR) experiments revealing that their interaction with the protein is not influenced by the presence of the anthranilic acid bound to active site cysteine. Importantly, some compounds reduced the signal molecule production in cellulo. Copyright © 2014. Published by Elsevier Masson SAS.
    No preview · Article · Nov 2014 · European Journal of Medicinal Chemistry
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    • "The ability to cause such a wide array of infections is dependent on the expression of virulence factors (Strateva and Mitov 2011). Virulence factor regulation in P. aeruginosa is achieved through a density-dependent cell-to-cell communication network, involving three main quorum-sensing systems; the las, rhl (Schuster et al. 2013; Smith and Iglewski 2003) and Pseudomonas quinolone signal system (Dubern and Diggle 2008; Pesci et al. 1999). The las and rhl systems are LuxRI homologues, where lasI and rhlI direct synthesis of N-3- oxododecanoylhomoserine lactone (3-oxo-C12-HSL) and Nbutanoylhomoserine lactone (C4-HSL), respectively; these are diffusible signalling molecules which activate their respective DNA binding response regulators, LasR and RhlR, which, in turn, induces the expression of a wide range of genes, approximately 6 % of the genome (Schuster and Greenberg 2006; Schuster et al. 2013; Wagner et al. 2004; Williams et al. 2007). "
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    ABSTRACT: Rhamnolipids (RLs) are heterogeneous glycolipid molecules that are composed of one or two L-rhamnose sugars and one or two β-hydroxy fatty acids, which can vary in their length and branch size. They are biosurfactants, predominantly produced by Pseudomonas aeruginosa and are important virulence factors, playing a major role in P. aeruginosa pathogenesis. Therefore, a fast, accurate and high-throughput method of detecting such molecules is of real importance. Here, we illustrate the ability to detect RL-producing P. aeruginosa strains with high sensitivity, based on an assay involving phospholipid vesicles encapsulated with a fluorescent dye. This vesicle-lysis assay is confirmed to be solely sensitive to RLs. We illustrate a half maximum concentration for vesicle lysis (EC50) of 40 μM (23.2 μg/mL) using pure commercial RLs and highlight the ability to semi-quantify RLs directly from the culture supernatant, requiring no extra extraction or processing steps or technical expertise. We show that this method is consistent with results from thin-layer chromatography detection and dry weight analysis of RLs but find that the widely used orcinol colorimetric test significantly underestimated RL quantity. Finally, we apply this methodology to compare RL production among strains isolated from either chronic or acute infections. We confirm a positive association between RL production and acute infection isolates (p = 0.0008), highlighting the role of RLs in certain infections.
    Full-text · Article · Jun 2014 · Applied Microbiology and Biotechnology
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    • "QS consists of a las and rhl N-acyl homoserine lactone system that produces 3-oxo-C12- and C4-homoserine lactones, respectively.24 The third QS 2-alkyl-4-quinolone system produces 2-heptyl-4-quinolone and Pseudomonas quinolone signal.25 These QS systems not only engage in intra-species communication within biofilms, but also affect other species and the host.26P. "
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    ABSTRACT: The use of antibiotics is unavoidable in trying to treat acute infections and in the prevention and control of chronic infections. Over the years, an ever increasing number of infections has escalated the use of antibiotics, which has necessitated action against an emerging bacterial resistance. There seems to be a continuous acquisition of new resistance mechanisms among bacteria that switch niches between human, animals, and the environment. An antibiotic resistant strain emerges when it acquires the DNA that confers the added capacity needed to survive in an unusual niche. Once acquired, a new resistance mechanism evolves according to the dynamics of the microenvironment; there is then a high probability that it is transferred to other species or to an avirulent strain of the same species. A well understood model for studying emerging antibiotic resistance and its impact is Pseudomonas aeruginosa, an opportunistic pathogen which is able to cause acute and chronic infections in nosocomial settings. This bacterium has a huge genetic repertoire consisting of genes that encode both innate and acquired antibiotic resistance traits. Besides acute infections, chronic colonization of P. aeruginosa in the lungs of cystic fibrosis (CF) patients plays a significant role in morbidity and mortality. Antibiotics used in the treatment of such infections has increased the longevity of patients over the last several decades. However, emerging multidrug resistant strains and the eventual increase in the dosage of antibiotic(s) is of major concern. Though there are various infections that are treated by single/combined antibiotics, the particular case of P. aeruginosa infection in CF patients serves as a reference for understanding the impact of overuse of antibiotics and emerging antibiotic resistant strains. This mini review presents the need for judicious use of antibiotics to treat various types of infections, protecting patients and the environment, as well as achieving a better treatment outcome.
    Full-text · Article · Apr 2013 · Microbiology Insights
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