title: Identity and effects of quorum-sensing inhibitors produced by Penicillium species.
abstract: Quorum sensing (QS) communication systems are thought to afford bacteria with a mechanism to strategically cause disease. One example is Pseudomonas aeruginosa, which infects immunocompromised individuals such as cystic fibrosis patients. The authors have previously documented that blockage of the QS systems not only attenuates Ps. aeruginosa but also renders biofilms highly susceptible to treatment with conventional antibiotics. Filamentous fungi produce a battery of secondary metabolites, some of which are already in clinical use as antimicrobial drugs. Fungi coexist with bacteria but lack active immune systems, so instead rely on chemical defence mechanisms. It was speculated that some of these secondary metabolites could interfere with bacterial QS communication. During a screening of 100 extracts from 50 Penicillium species, 33 were found to produce QS inhibitory (QSI) compounds. In two cases, patulin and penicillic acid were identified as being biologically active QSI compounds. Their effect on QS-controlled gene expression in Ps. aeruginosa was verified by DNA microarray transcriptomics. Similar to previously investigated QSI compounds, patulin was found to enhance biofilm susceptibility to tobramycin treatment. Ps. aeruginosa has developed QS-dependent mechanisms that block development of the oxidative burst in PMN neutrophils. Accordingly, when the bacteria were treated with either patulin or penicillic acid, the neutrophils became activated. In a mouse pulmonary infection model, Ps. aeruginosa was more rapidly cleared from the mice that were treated with patulin compared with the placebo group.
authors.affiliation: Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Thomas Bovbjerg
authors.initials: TB
authors.lastname: Rasmussen
authors.affiliation: Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Mette E
authors.initials: ME
authors.lastname: Skindersoe
authors.affiliation: Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bjarnsholt
authors.affiliation: Center for Microbial Biotechnology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Phipps
authors.affiliation: Center for Microbial Biotechnology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Kathrine Bisgaard
authors.initials: KB
authors.lastname: Christensen
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, DK-2100, Copenhagen Ø, Denmark.
authors.forename: Peter Ostrup
authors.initials: PO
authors.lastname: Jensen
authors.affiliation: Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Jens Bo
authors.initials: JB
authors.lastname: Andersen
authors.affiliation: Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Birgit
authors.initials: B
authors.lastname: Koch
authors.affiliation: Center for Microbial Biotechnology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Thomas Ostenfeld
authors.initials: TO
authors.lastname: Larsen
authors.affiliation: Carlsberg Research Center, Biosector, Gamle Carlsberg Vej 10, DK-2500 Valby, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Hentzer
authors.affiliation: Department of Microbiology, University of Zürich, CH-8008 Zürich, Switzerland.
authors.forename: Leo
authors.initials: L
authors.lastname: Eberl
authors.affiliation: Department of Bacteriology, Institute of Medical Microbiology and Immunology, University of Copenhagen, Denmark.|Department of Clinical Microbiology, Rigshospitalet, DK-2100, Copenhagen Ø, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Hoiby
authors.affiliation: Center for Biomedical Microbiology, BioCentrum-DTU, Technical University of Denmark, DK-2800 Kgs. Lyngby, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Givskov
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D005260:Female; D015964:Gene Expression Regulation, Bacterial; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009504:Neutrophils / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D010365:Patulin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010398:Penicillic Acid / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010407:Penicillium / Q000145:classification / Q000378:metabolism*; D020543:Proteome; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000276:immunology / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D020543:Proteome; D010365:Patulin; D010398:Penicillic Acid