title: Quaternary ammonium surfactant structure determines selective toxicity towards bacteria: mechanisms of action and clinical implications in antibacterial prophylaxis.
abstract: OBJECTIVE
  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.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Ângela S
authors.initials: ÂS
authors.lastname: Inácio
authors.affiliation: CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
authors.forename: Neuza S
authors.initials: NS
authors.lastname: Domingues
authors.affiliation: Department of Infectious Diseases, National Institute of Health, Lisbon, Portugal.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Nunes
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: Patrícia T
authors.initials: PT
authors.lastname: Martins
authors.affiliation: Centro de Química de Coimbra and Departamento de Química, Universidade de Coimbra, 3004-535 Coimbra, Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Moreno
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors.forename: Luís M
authors.initials: LM
authors.lastname: Estronca
authors.affiliation: IBMC/HEMS - Instituto de Biologia Molecular e Celular/Histology and Electron Microscopy Service, Universidade do Porto, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Fernandes
authors.affiliation: Department of Life Sciences, University of Coimbra, Coimbra, Portugal.
authors.forename: António J M
authors.initials: AJ
authors.lastname: Moreno
authors.affiliation: Department of Infectious Diseases, National Institute of Health, Lisbon, Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Borrego
authors.affiliation: Department of Infectious Diseases, National Institute of Health, Lisbon, Portugal.
authors.forename: João P
authors.initials: JP
authors.lastname: Gomes
authors.affiliation: CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal.
authors.forename: Winchil L C
authors.initials: WL
authors.lastname: Vaz
authors.affiliation: CEDOC, NOVA Medical School | Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, 1169-056 Lisboa, Portugal otilia.vieira@fcm.unl.pt.
authors.forename: Otília V
authors.initials: OV
authors.lastname: Vieira
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000891:Anti-Infective Agents, Local / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008660:Metabolism / Q000187:drug effects; D050296:Microbial Viability / Q000187:drug effects; D009344:Neisseria gonorrhoeae / Q000187:drug effects / Q000502:physiology; D000644:Quaternary Ammonium Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013501:Surface-Active Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D000644:Quaternary Ammonium Compounds; D013501:Surface-Active Agents