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      Targeting Staphylococcus aureus Quorum Sensing with Nonpeptidic Small Molecule Inhibitors

      rapid-communication

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          Abstract

          A series of 3-oxo-C 12-HSL, tetramic acid, and tetronic acid analogues were synthesized to gain insights into the structural requirements for quorum sensing inhibition in Staphylococcus aureus . Compounds active against agr were noncompetitive inhibitors of the autoinducing peptide (AIP) activated AgrC receptor, by altering the activation efficacy of the cognate AIP-1. They appeared to act as negative allosteric modulators and are exemplified by 3-tetradecanoyltetronic acid 17, which reduced nasal cell colonization and arthritis in a murine infection model.

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          Iron and microbial infection.

          Ulrich E. Schaible, Stefan Kaufmann (2004)
          The use of iron as a cofactor in basic metabolic pathways is essential to both pathogenic microorganisms and their hosts. It is also a pivotal component of the innate immune response through its role in the generation of toxic oxygen and nitrogen intermediates. During evolution, the shared requirement of micro- and macroorganisms for this important nutrient has shaped the pathogen-host relationship. Here, we discuss how pathogens compete with the host for iron, and also how the host uses iron to counteract this threat.
          Article 0 comments Cited 267 times – based on 0 reviews     Review now
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            Quorum sensing and environmental adaptation in Pseudomonas aeruginosa: a tale of regulatory networks and multifunctional signal molecules.

            Paul Williams, Miguel Cámara (2009)
            Bacteria employ sophisticated cell-to-cell communication or 'quorum sensing' (QS) systems for promoting collective behaviours that depend on the actions of one or more chemically distinct diffusible signal molecules. As determinants of cell population density, multiple QS systems are often integrated with each other and within global regulatory networks and subject to the prevailing environmental conditions as well as the presence and activities of other organisms. QS signal molecules, although largely considered as effectors of QS-dependent gene expression are also emerging as multifunctional molecules that influence life, development and death in single and mixed microbial populations and impact significantly the outcome of host-pathogen interactions.
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              Look who's talking: communication and quorum sensing in the bacterial world.

              Paul Williams, Klaus Winzer, Weng C. Chan … (2007)
              For many years bacteria were considered primarily as autonomous unicellular organisms with little capacity for collective behaviour. However, we now appreciate that bacterial cells are in fact, highly communicative. The generic term 'quorum sensing' has been adopted to describe the bacterial cell-to-cell communication mechanisms which co-ordinate gene expression usually, but not always, when the population has reached a high cell density. Quorum sensing depends on the synthesis of small molecules (often referred to as pheromones or autoinducers) that diffuse in and out of bacterial cells. As the bacterial population density increases, so does the synthesis of quorum sensing signal molecules, and consequently, their concentration in the external environment rises. Once a critical threshold concentration has been reached, a target sensor kinase or response regulator is activated (or repressed) so facilitating the expression of quorum sensing-dependent genes. Quorum sensing enables a bacterial population to mount a co-operative response that improves access to nutrients or specific environmental niches, promotes collective defence against other competitor prokaryotes or eukaryotic defence mechanisms and facilitates survival through differentiation into morphological forms better able to combat environmental threats. Quorum sensing also crosses the prokaryotic-eukaryotic boundary since quorum sensing-dependent signalling can be exploited or inactivated by both plants and mammals.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Med Chem
                Journal ID (iso-abbrev): J. Med. Chem
                Journal ID (publisher-id): jm
                Journal ID (coden): jmcmar
                Title: Journal of Medicinal Chemistry
                Publisher: American Chemical Society
                ISSN (Print): 0022-2623
                ISSN (Electronic): 1520-4804
                Publication date (Electronic): 04 March 2014
                Publication date (Print): 27 March 2014
                Volume: 57
                Issue: 6
                Pages: 2813-2819
                Affiliations
                [† ]School of Life Sciences, Centre for Biomolecular Sciences, University of Nottingham , Nottingham, NG7 2RD, U.K.
                [‡ ]School of Pharmacy, Centre for Biomolecular Sciences, University of Nottingham , Nottingham, NG7 2RD, U.K.
                [§ ]School of Life Sciences, University of Nottingham , University Park, Nottingham, NG7 2RD, U.K.
                [∥ ]Department of Rheumatology and Inflammation Research, University of Gothenburg , Gothenburg 40530, Sweden
                Author notes
                [* ]W.C.C.: phone, +44-115-9515080; e-mail, weng.chan@ 123456nottingham.ac.uk .
                [* ]P.W.: phone, +44-115-9515047; e-mail, paul.williams@ 123456nottingham.ac.uk .
                Article
                DOI: 10.1021/jm500215s
                PMC ID: 4010551
                PubMed ID: 24592914
                SO-VID: ff7553e3-b0ef-43f0-b405-e8b415d85c68
                Copyright © Copyright © 2014 American Chemical Society
                License:

                Terms of Use CC-BY

                History
                Date received : 19 December 2013
                Categories
                Subject: Brief Article
                Custom metadata
                document-id-old-9 jm500215s
                document-id-new-14 jm-2014-00215s
                ccc-price

                ScienceOpen disciplines: Pharmaceutical chemistry
                Data availability:
                ScienceOpen disciplines: Pharmaceutical chemistry

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