Higgins, D.A. et al. The major Vibrio cholerae autoinducer and its role in virulence factor production. Nature 450, 883-886

Department of Chemistry, Princeton University, Princeton, New Jersey, United States
Nature (Impact Factor: 41.46). 01/2008; 450(7171):883-6. DOI: 10.1038/nature06284
Source: PubMed

ABSTRACT Vibrio cholerae, the causative agent of the human disease cholera, uses cell-to-cell communication to control pathogenicity and biofilm formation. This process, known as quorum sensing, relies on the secretion and detection of signalling molecules called autoinducers. At low cell density V. cholerae activates the expression of virulence factors and forms biofilms. At high cell density the accumulation of two quorum-sensing autoinducers represses these traits. These two autoinducers, cholerae autoinducer-1 (CAI-1) and autoinducer-2 (AI-2), function synergistically to control gene regulation, although CAI-1 is the stronger of the two signals. V. cholerae AI-2 is the furanosyl borate diester (2S,4S)-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran borate. Here we describe the purification of CAI-1 and identify the molecule as (S)-3-hydroxytridecan-4-one, a new type of bacterial autoinducer. We provide a synthetic route to both the R and S isomers of CAI-1 as well as simple homologues, and we evaluate their relative activities. Synthetic (S)-3-hydroxytridecan-4-one functions as effectively as natural CAI-1 in repressing production of the canonical virulence factor TCP (toxin co-regulated pilus). These findings suggest that CAI-1 could be used as a therapy to prevent cholera infection and, furthermore, that strategies to manipulate bacterial quorum sensing hold promise in the clinical arena.

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    • "The formation of V. cholerae biofilm is induced at low cell density and repressed at high cell density (Ng and Bassler 2009). The Vibrio QS system is composed of two sensory circuits that respond to two different autoinducers: Als–AI-2 or a hydroxylated alkyl ketone, CAI-1 (Higgins et al. 2007; Tiaden et al. 2010). At low concentrations of inducers, the periplasmic receptors, respectively, histidine kinases LuxPQ and CpqS, phosphorylate the response regulator LuxO. "
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    ABSTRACT: Nearly all bacterial species, including pathogens, have the ability to form biofilms. Biofilms are defined as structured ecosystems in which microbes are attached to surfaces and embedded in a matrix composed of polysaccharides, eDNA, and proteins, and their development is a multistep process. Bacterial biofilms constitute a large medical problem due to their extremely high resistance to various types of therapeutics, including conventional antibiotics. Several environmental and genetic signals control every step of biofilm development and dispersal. From among the latter, quorum sensing, cyclic diguanosine-5'-monophosphate, and small RNAs are considered as the main regulators. The present review describes the control role of these three regulators in the life cycles of biofilms built by Pseudomonas aeruginosa, Staphylococcus aureus, Salmonella enterica serovar Typhimurium, and Vibrio cholerae. The interconnections between their activities are shown. Compounds and strategies which target the activity of these regulators, mainly quorum sensing inhibitors, and their potential role in therapy are also assessed.
    Journal of applied genetics 08/2015; DOI:10.1007/s13353-015-0309-2 · 1.48 Impact Factor
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    • "Virulence factors are tools used by pathogenic bacteria to facilitate disease in plants, animals, and man (Higgins et al., 2007; Raghavan, Manzanillo, Chan, Dovey & Cox, 2008; Tsigrelis, Singh, Coutinho, Murray & Baddour, 2007; Yahr & Wolfgang, 2006); one strategy to combat infection is to inhibit these factors by small molecule therapy, thereby helping to neutralize the offending microbe (Benghezal et al., 2007; Cegelski, Marshall, Eldridge & Hultgren, 2008; Escaich, 2008; Kollef, 2008; Maresso & Schneewind, 2008). It is now generally appreciated that an antivirulence approach is a powerful alternative strategy to antibacterial treatment and vaccine development (Rappuoli, 2007) and that it may require multiple tactics to resolve the current drug resistance dilemma (Cegelski et al., 2008; Clatworthy, Pierson & Hung, 2007). "
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    ABSTRACT: Abstract Cholix toxin from V. cholerae, is the third member of the diphtheria toxin group of mono-ADP-ribosyltransferase bacterial toxins. It shares structural and functional properties with P. aeruginosa exotoxin A and C. diphtheriae diphtheria toxin. Cholix toxin is an important model for the development of antivirulence approaches and therapeutics against these toxins from pathogenic bacteria. Herein, we have used the high-resolution X-ray structure of full-length cholix complexed with NAD(+) to describe the properties of the NAD(+)-binding pocket at the residue level, including the role of crystallographic water molecules in the NAD(+) substrate interaction. The full length apo cholix structure is used to describe the putative NAD(+) binding site(s) and to correlate biochemical with crystallographic data to study the stoichiometry and orientation of bound NAD(+) molecules. We quantitatively describe the NAD(+) substrate interactions on a residue basis for the main 22 pocket residues in cholixf, a glycerol and 5 contact water molecules as part of the recognition surface by the substrate according to the conditions of crystallization. In addition, the dynamic properties of an in silico version of the catalytic domain were investigated in order to understand the lack of electronic density for one of the main flexible loops (R-loop) in the pocket of X-ray complexes. Implications for a rational drug design approach for mART toxins are derived.
    Journal of biomolecular Structure & Dynamics 01/2015; 23:1-0. DOI:10.1080/07391102.2014.1000972 · 2.92 Impact Factor
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    • "QS regulation of Harveyi clade Vibrio spp. is rather complex. These bacteria produce and respond to three autoinducers (AIs): HAI-1 (N-[β-hydroxybutyryl] homoserine lactone), a species-specific AI [24]–[25], CAI-1 ([S]-3-hydroxytridecan-4-one), a genus-specific signal [16]–[17], and AI-2 ([2S,4S]-2-methyl-2,3,3,4-tetrahydroxytetrahydrofuran borate), an interspecies signal [18]–[20]. "
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    ABSTRACT: In this study, the evidence of electron-dense magnetic inclusions with polyhedral shape in the cytoplasm of Harveyi clade Vibrio strain PS1, a bioluminescent bacterium living in symbiosis with marine organisms, led us to investigate the behavior of this bacterium under exposure to static magnetic fields ranging between 20 and 2000 Gauss. When compared to sham-exposed, the light emission of magnetic field-exposed bacteria growing on solid medium at 18°C ±0.1°C was increased up to two-fold as a function of dose and growth phase. Stimulation of bioluminescence by magnetic field was more pronounced during the post-exponential growth and stationary phase, and was lost when bacteria were grown in the presence of the iron chelator deferoxamine, which caused disassembly of the magnetic inclusions suggesting their involvement in magnetic response. As in luminescent Vibrio spp. bioluminescence is regulated by quorum sensing, possible effects of magnetic field exposure on quorum sensing were investigated. Measurement of mRNA levels by reverse transcriptase real time-PCR demonstrated that luxR regulatory gene and luxCDABE operon coding for luciferase and fatty acid reductase complex were significantly up-regulated in magnetic field-exposed bacteria. In contrast, genes coding for a type III secretion system, whose expression was negatively affected by LuxR, were down-regulated. Up-regulation of luxR paralleled with down-regulation of small RNAs that mediate destabilization of luxR mRNA in quorum sensing signaling pathways. The results of experiments with the well-studied Vibrio campbellii strain BB120 (originally classified as Vibrio harveyi) and derivative mutants unable to synthesize autoinducers suggest that the effects of magnetic fields on quorum sensing may be mediated by AI-2, the interspecies quorum sensing signal molecule.
    PLoS ONE 06/2014; 9(6):e100825. DOI:10.1371/journal.pone.0100825 · 3.23 Impact Factor
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