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Article: Inhibitors of pathogen intercellular signals as selective anti-infective compounds

TitleInhibitors of pathogen intercellular signals as selective anti-infective compounds
Authors
Issue Date2007
PublisherPublic Library of Science. The Journal's web site is located at http://pathogens.plosjournals.org/perlserv/?request=index-html&issn=1553-7374
Citation
Plos Pathogens, 2007, v. 3 n. 9, p. 1229-1239 How to Cite?
AbstractLong-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens. © 2007 Lesic et al.
Persistent Identifierhttp://hdl.handle.net/10722/180728
ISSN
2015 Impact Factor: 7.003
2015 SCImago Journal Rankings: 5.185
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorLesic, Ben_US
dc.contributor.authorLépine, Fen_US
dc.contributor.authorDéziel, Een_US
dc.contributor.authorZhang, Jen_US
dc.contributor.authorZhang, Qen_US
dc.contributor.authorPadfield, Ken_US
dc.contributor.authorCastonguay, MHen_US
dc.contributor.authorMilot, Sen_US
dc.contributor.authorStachel, Sen_US
dc.contributor.authorTzika, AAen_US
dc.contributor.authorTompkins, RGen_US
dc.contributor.authorRahme, LGen_US
dc.date.accessioned2013-01-28T01:42:03Z-
dc.date.available2013-01-28T01:42:03Z-
dc.date.issued2007en_US
dc.identifier.citationPlos Pathogens, 2007, v. 3 n. 9, p. 1229-1239en_US
dc.identifier.issn1553-7366en_US
dc.identifier.urihttp://hdl.handle.net/10722/180728-
dc.description.abstractLong-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens. © 2007 Lesic et al.en_US
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://pathogens.plosjournals.org/perlserv/?request=index-html&issn=1553-7374en_US
dc.relation.ispartofPLoS Pathogensen_US
dc.subject.meshAnimalsen_US
dc.subject.meshAnti-Bacterial Agents - Pharmacology - Therapeutic Useen_US
dc.subject.meshCell Survival - Physiologyen_US
dc.subject.meshGene Expression Regulation, Bacterialen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Inbred Strainsen_US
dc.subject.meshPseudomonas Infections - Drug Therapyen_US
dc.subject.meshPseudomonas Aeruginosa - Genetics - Physiologyen_US
dc.subject.meshQuinolines - Metabolismen_US
dc.subject.meshQuorum Sensing - Drug Effects - Physiologyen_US
dc.subject.meshVirulenceen_US
dc.subject.meshVirus Cultivationen_US
dc.subject.meshOrtho-Aminobenzoates - Chemistry - Metabolismen_US
dc.titleInhibitors of pathogen intercellular signals as selective anti-infective compoundsen_US
dc.typeArticleen_US
dc.identifier.emailZhang, J: jzhang1@hku.hken_US
dc.identifier.authorityZhang, J=rp01713en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1371/journal.ppat.0030126en_US
dc.identifier.pmid17941706-
dc.identifier.scopuseid_2-s2.0-34848815010en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-34848815010&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume3en_US
dc.identifier.issue9en_US
dc.identifier.spage1229en_US
dc.identifier.epage1239en_US
dc.identifier.isiWOS:000249768300006-
dc.publisher.placeUnited Statesen_US
dc.identifier.f1000718180365-
dc.identifier.scopusauthoridLesic, B=15074166900en_US
dc.identifier.scopusauthoridLépine, F=7006611357en_US
dc.identifier.scopusauthoridDéziel, E=6602634781en_US
dc.identifier.scopusauthoridZhang, J=22137260600en_US
dc.identifier.scopusauthoridZhang, Q=8558801500en_US
dc.identifier.scopusauthoridPadfield, K=8558801400en_US
dc.identifier.scopusauthoridCastonguay, MH=15074123400en_US
dc.identifier.scopusauthoridMilot, S=6603387958en_US
dc.identifier.scopusauthoridStachel, S=36722572800en_US
dc.identifier.scopusauthoridTzika, AA=7003635500en_US
dc.identifier.scopusauthoridTompkins, RG=7101805272en_US
dc.identifier.scopusauthoridRahme, LG=6603919311en_US

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