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Quaternary ammonium surfactant structure determines selective toxicity towards bacteria: mechanisms of action and clinical implications in antibacterial prophylaxis

2016-03Journal article Restricted access
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dc.contributor.authorInácio, Ângela S.
dc.contributor.authorDomingues, Neuza S.
dc.contributor.authorNunes, Alexandra
dc.contributor.authorMartins, Patrícia T.
dc.contributor.authorMoreno, Maria J.
dc.contributor.authorEstronca, Luís M.
dc.contributor.authorFernandes, Rui
dc.contributor.authorMoreno, António J.M.
dc.contributor.authorBorrego, Maria José
dc.contributor.authorGomes, João Paulo
dc.contributor.authorVaz, Winchil L.C.
dc.contributor.authorVieira, Otília V.
dc.date.accessioned2016-02-19T12:31:30Z
dc.date.available2016-02-19T12:31:30Z
dc.date.issued2016-03
dc.description.abstractObjectives: Broad-spectrum antimicrobial activity of quaternary ammonium surfactants (QAS) makes them attractive and cheap topical prophylactic options for sexually transmitted infections and perinatal vertically transmitted urogenital infections. Although attributed to their high affinity for biological membranes, the mechanisms behind QAS microbicidal activity are not fully understood. We evaluated how QAS structure affects antimicrobial activity and whether this can be exploited for use in prophylaxis of bacterial infections. Methods: Acute toxicity of QAS to in vitro models of human epithelial cells and bacteria were compared to identify selective and potent bactericidal agents. Bacterial cell viability, membrane integrity, cell cycle and metabolism were evaluated to establish the mechanisms involved in selective toxicity of QAS. Results: QAS toxicity normalized relative to surfactant critical micelle concentration showed n-dodecylpyridinium bromide (C12PB) to be the most effective, with a therapeutic index of ∼10 for an MDR strain of Escherichia coli and >20 for Neisseria gonorrhoeae after 1 h of exposure. Three modes of QAS antibacterial action were identified: impairment of bacterial energetics and cell division at low concentrations; membrane permeabilization and electron transport inhibition at intermediate doses; and disruption of bacterial membranes and cell lysis at concentrations close to the critical micelle concentration. In contrast, toxicity to mammalian cells occurs at higher concentrations and, as we previously reported, results primarily from mitochondrial dysfunction and apoptotic cell death. Conclusions: Our data show that short chain (C12) n-alkyl pyridinium bromides have a sufficiently large therapeutic window to be good microbicide candidates.pt_PT
dc.description.sponsorshipThis work was supported by the Foundation for Science and Technology of the Portuguese Ministry of Science and Higher Education (HMSP-ICT/0024/2010, PTDC/BIA-BCM/112138/2009 and UID/QUI/00313/2013); Inova4Health; and the University of Coimbra, Coimbra, Portugal (Bolsa de Ignição INOV.C 2011), co-founded by the European Union (FEDER-Fundo Europeu de Desenvolvimento Regional) through COMPETE-Programa Operacional Factores de Competitividade and QREN-Quadro de Referência Estratégico Nacional.pt_PT
dc.identifier.citationJ Antimicrob Chemother. 2016 Mar;71(3):641-54. doi: 10.1093/jac/dkv405. Epub 2015 Dec 17pt_PT
dc.identifier.doi10.1093/jac/dkv405pt_PT
dc.identifier.issn0305-7453
dc.identifier.urihttp://hdl.handle.net/10400.18/3438
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherOxford University Press/ British Society for Antimicrobial Chemotherapypt_PT
dc.relationA New Approach to Fight Tuberculosis
dc.relation.publisherversionhttps://jac.oxfordjournals.org/content/71/3/641.abstractpt_PT
dc.subjectQASpt_PT
dc.subjectProphylaxispt_PT
dc.subjectToxicitypt_PT
dc.subjectGenitalpt_PT
dc.subjectCritical Micelle Concentrationpt_PT
dc.subjectAnti-bacterial Prophylaxispt_PT
dc.subjectTopical Microbicidespt_PT
dc.subjectInfecções Sexualmente Transmissíveispt_PT
dc.titleQuaternary ammonium surfactant structure determines selective toxicity towards bacteria: mechanisms of action and clinical implications in antibacterial prophylaxispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleA New Approach to Fight Tuberculosis
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/HMSP-ICT%2F0024%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876-PPCDTI/PTDC%2FBIA-BCM%2F112138%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5876/UID%2FQUI%2F00313%2F2013/PT
oaire.citation.endPage654pt_PT
oaire.citation.startPage641pt_PT
oaire.citation.titleJournal of Antimicrobial Chemotherapypt_PT
oaire.citation.volume71(3)pt_PT
oaire.fundingStream5876-PPCDTI
oaire.fundingStream5876-PPCDTI
oaire.fundingStream5876
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationd4cd071f-2e7d-40af-ab89-d4fa7ec1c6c9
relation.isProjectOfPublication0edbc0d4-796f-490b-868c-f9943c2a9b44
relation.isProjectOfPublication0a0b6cbe-15f2-4501-8755-e39b05c564ea
relation.isProjectOfPublication.latestForDiscovery0edbc0d4-796f-490b-868c-f9943c2a9b44

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