title: Inhibition of the production of the Pseudomonas aeruginosa virulence factor pyocyanin in wild-type cells by quorum sensing autoinducer-mimics.
abstract: Pseudomonas aeruginosa is a notorious human pathogen associated with a range of life-threatening nosocomial infections. There is an increasing problem of antibiotic resistance in P. aeruginosa, highlighted by the emergence of multi-drug resistant strains. Thus the exploration of new strategies for the treatment of P. aeruginosa infections is clearly warranted. P. aeruginosa is known to produce a range of virulence factors that enhance its ability to damage the host tissue and cause disease. One of the most important virulence factors is pyocyanin. P. aeruginosa regulates pyocyanin production using an intercellular communication mechanism called quorum sensing, which is mediated by small signalling molecules termed autoinducers. One native autoinducer is N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). Herein we report the synthesis of a collection of abiotic OdDHL-mimics. A number of novel compounds capable of competing with the endogenous OdDHL and consequently, inhibiting the production of pyocyanin in cultures of wild type P. aeruginosa were identified. We present evidence suggesting that compounds of this general structural type act as direct antagonists of quorum sensing in P. aeruginosa and as such may find value as molecular tools for the study and manipulation of this signalling pathway. A direct quantitative comparison of the pyocyanin suppressive activities of the most active OdDHL-mimics with some previously-reported inhibitors (based around different general structural frameworks) of quorum sensing from the literature, was also made.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK.
authors.forename: Bernardas
authors.initials: B
authors.lastname: Morkunas
authors.forename: Warren R J D
authors.initials: WR
authors.lastname: Galloway
authors.forename: Megan
authors.initials: M
authors.lastname: Wright
authors.forename: Brett M
authors.initials: BM
authors.lastname: Ibbeson
authors.forename: James T
authors.initials: JT
authors.lastname: Hodgkinson
authors.forename: Kieron M G
authors.initials: KM
authors.lastname: O'Connell
authors.forename: Noemi
authors.initials: N
authors.lastname: Bartolucci
authors.forename: Martina
authors.initials: M
authors.lastname: Della Valle
authors.forename: Martin
authors.initials: M
authors.lastname: Welch
authors.forename: David R
authors.initials: DR
authors.lastname: Spring
mesh_terms: D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006714:Homoserine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000378:metabolism / Q000472:pathogenicity; D011710:Pyocyanine / Q000378:metabolism*; D053038:Quorum Sensing / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D037521:Virulence Factors / Q000378:metabolism*
chemical_list: C109860:N-(3-oxododecanoyl)homoserine lactone; D054852:Small Molecule Libraries; D037521:Virulence Factors; D006714:Homoserine; D011710:Pyocyanine; D015107:4-Butyrolactone