Quinolones: from antibiotics to autoinducers. FEMS Microbiol Rev

School of Molecular Medical Sciences, Centre for Biomolecular Sciences, University Park, University of Nottingham, Nottingham, UK.
FEMS microbiology reviews (Impact Factor: 13.24). 03/2011; 35(2):247-74. DOI: 10.1111/j.1574-6976.2010.00247.x
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Since quinine was first isolated, animals, plants and microorganisms producing a wide variety of quinolone compounds have been discovered, several of which possess medicinally interesting properties ranging from antiallergenic and anticancer to antimicrobial activities. Over the years, these have served in the development of many synthetic drugs, including the successful fluoroquinolone antibiotics. Pseudomonas aeruginosa and related bacteria produce a number of 2-alkyl-4(1H)-quinolones, some of which exhibit antimicrobial activity. However, quinolones such as the Pseudomonas quinolone signal and 2-heptyl-4-hydroxyquinoline act as quorum-sensing signal molecules, controlling the expression of many virulence genes as a function of cell population density. Here, we review selectively this extensive family of bicyclic compounds, from natural and synthetic antimicrobials to signalling molecules, with a special emphasis on the biology of P. aeruginosa. In particular, we review their nomenclature and biochemistry, their multiple properties as membrane-interacting compounds, inhibitors of the cytochrome bc(1) complex and iron chelators, as well as the regulation of their biosynthesis and their integration into the intricate quorum-sensing regulatory networks governing virulence and secondary metabolite gene expression.

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    • "AQs have low water solubility, are mostly associated with the bacterial outer membrane and can be trafficked between cells in membrane vesicles (MVs) (Lépine et al., 2003; Mashburn-Warren et al., 2008). AQ biosynthesis requires the products of the pqsABCDE operon, apart from pqsE, which codes for an effector protein of unknown function required for the AQ response (Heeb et al., 2011). PqsA, B, C and D are all required for the production of AQs such as the C7 congener, 2-heptyl-4-hydroxyquinoline (HHQ), that are subsequently oxidized to 3-hydroxy congeners such as 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS) by the monooxygenase, PqsH (Heeb et al., 2011). "
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    ABSTRACT: In Pseudomonas aeruginosa quorum sensing (QS) regulates the production of secondary metabolites, many of which are antimicrobials that impact on polymicrobial community composition. Consequently, quenching QS modulates the environmental impact of P.aeruginosa. To identify bacteria capable of inactivating the QS signal molecule 2-heptyl-3-hydroxy-4(1H)-quinolone (PQS), a minimal medium containing PQS as the sole carbon source was used to enrich a Malaysian rainforest soil sample. This yielded an Achromobacter xylosoxidans strain (Q19) which inactivated PQS yielding a new fluorescent compound (I-PQS) confirmed as PQS-derived using deuterated-PQS. The I-PQS structure was elucidated using MS and NMR as 2-heptyl-2-hydroxy-1,2-dihydroquinoline-3,4-dione (HHQD). A. xylosoxidans Q19 oxidized PQS congeners with alkyl chains ranging from C1 to C5 and also N-methyl PQS yielding the corresponding 2-hydroxy-1,2-dihydroquinoline-3,4-diones, but was unable to inactivate the PQS precursor HHQ. This indicates that the hydroxyl group at position 3 in PQS is essential and that A.xylosoxidans inactivates PQS via a pathway involving the incorporation of oxygen at C2 of the heterocyclic ring. The conversion of PQS to HHQD also occurred on incubation with 12/17 A.xylosoxidans strains recovered from cystic fibrosis patients, with P.aeruginosa and with Arthrobacter, suggesting that formation of hydroxylated PQS may be a common mechanism of inactivation. This article is protected by copyright. All rights reserved.
    Environmental Microbiology 03/2015; DOI:10.1111/1462-2920.12857 · 6.20 Impact Factor
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    • "The N-acylhomoserine lactones are the corresponding signals of the core of QS, the hierarchical las and rhl systems. With respect to AHQs, they include the most active signal 2-heptyl-3-hydroxi-4- quinolone, also known as the Pseudomonas quinolone signal or PQS, and its precursor 2-heptyl-4-quinolone (HHQ) [12]. PQS provides a link between las and rhl, being activated by las and repressed by rhl [9]. "
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    ABSTRACT: One of the main stress factors that bacteria face in the environment is solar ultraviolet-A (UVA) radiation, which leads to lethal effects through oxidative damage. The aim of this work was to investigate the role of 2-heptyl-3-hydroxi-4-quinolone (the Pseudomonas quinolone signal or PQS) in the response of Pseudomonas aeruginosa to UVA radiation. PQS is an intercellular quorum sensing signal associated to membrane vesicles which, among other functions, regulates genes related to iron acquisition, forms stable complexes with iron and participates in oxidative phenomena. UVA exposure of the wild-type PAO1 strain and a pqsA mutant unable to produce PQS revealed a sensitising role for this signal. Research into the mechanism involved in this phenomenon revealed that catalase, an essential factor in the UVA defence, is not related to PQS-mediated UVA sensitivity. Absorption of UVA by PQS produced its own photo-degradation, oxidation of the probe 2',7'- dichlorodihydrofluorescein and generation of singlet oxygen and superoxide anion, suggesting that this signal could be acting as an endogenous photosensitiser. The results presented in this study could explain the high sensitivity to UVA of P. aeruginosa when compared to enteric bacteria. Copyright © 2014 Elsevier B.V. All rights reserved.
    Journal of Photochemistry and Photobiology B Biology 12/2014; 142C:129-140. DOI:10.1016/j.jphotobiol.2014.11.014 · 2.96 Impact Factor
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    • "Multiple roles have been attributed to alkaloids in the above organisms, most related to self-preservation, inhibition of competitors , or communication. In micro-organisms, for example, alkaloids act as feeding deterrents [33], allelochemicals, autoinducers and siderophores [34]. In plants, the inhibitory effects of alkaloids on glycosidase and trehalose metabolism deter herbivores [35], and the ability to quench singlet oxygen confers protection against this toxic photosynthetic byproduct [18]. "
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    ABSTRACT: With reports of pandrug-resistant bacteria causing untreatable infections, the need for new antibacterial therapies is more pressing than ever. Alkaloids are a large and structurally diverse group of compounds that have served as scaffolds for important antibacterial drugs such as metronidazole and the quinolones. In this review, we highlight other alkaloids with development potential. Natural, semisynthetic and synthetic alkaloids of all classes are considered, looking first at those with direct antibacterial activity and those with antibiotic-enhancing activity. Potent examples include CJ-13,136, a novel actinomycete-derived quinolone alkaloid with a minimum inhibitory concentration of 0.1 ng/mL against Helicobacter pylori, and squalamine, a polyamine alkaloid from the dogfish shark that renders Gram-negative pathogens 16- to >32-fold more susceptible to ciprofloxacin. Where available, information on toxicity, structure–activity relationships, mechanisms of action and in vivo activity is presented. The effects of alkaloids on virulence gene regulatory systems such as quorum sensing and virulence factors such as sortases, adhesins and secretion systems are also described. The synthetic isoquinoline alkaloid virstatin, for example, inhibits the transcriptional regulator ToxT in Vibrio cholerae, preventing expression of cholera toxin and fimbriae and conferring in vivo protection against intestinal colonisation. The review concludes with implications and limitations of the described research and directions for future research.
    International Journal of Antimicrobial Agents 11/2014; 44(5). DOI:10.1016/j.ijantimicag.2014.06.001 · 4.30 Impact Factor
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