title: Clinical concentrations of thioridazine enhance the killing of intracellular methicillin-resistant Staphylococcus aureus: an in vivo, ex vivo and electron microscopy study.
abstract: Chlorpromazine (CPZ) is concentrated by human macrophages where it kills intracellular mycobacteria when the concentration outside the macrophage is sub-clinical. We have previously demonstrated that thioridazine (TZ), a much milder phenothiazine, has similar activity and kills intracellular methicillin-susceptible S. aureus at sub-clinical concentrations. We have extended this latter study to include methicillin-resistant S. aureus (MRSA) and show that TZ kills intracellular MRSA at clinically relevant concentrations. The ultrastructure of MRSA exposed to in vitro concentrations of TZ just below its MIC and that of MRSA phagocytosed by macrophages previously exposed to a clinically relevant concentration of TZ was also studied. TZ inhibits the replication of phagocytosed MRSA, affecting the structure of the cell envelope, resulting in lysis of the bacterium 6 hours post-phagocytosis. These ultrastructural changes are identical to those produced in vitro by a TZ concentration that is just below the MIC. Because macrophage intracellular MRSA is not killed by the macrophage and its intracellular location protects it from antibiotics that are unable to reach that site, recurrent infections which result may be successfully managed with the use of TZ.
authors.affiliation: Unit of Mycobacteriology, UPMM, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, 1349-019 Lisboa, Portugal.
authors.forename: Marta
authors.initials: M
authors.lastname: Martins
authors.forename: Wilfrid
authors.initials: W
authors.lastname: Bleiss
authors.forename: Anorte
authors.initials: A
authors.lastname: Marko
authors.forename: Diane
authors.initials: D
authors.lastname: Ordway
authors.forename: Miguel
authors.initials: M
authors.lastname: Viveiros
authors.forename: Clara
authors.initials: C
authors.lastname: Leandro
authors.forename: Teresa
authors.initials: T
authors.lastname: Pacheco
authors.forename: Joseph
authors.initials: J
authors.lastname: Molnar
authors.forename: Jette E
authors.initials: JE
authors.lastname: Kristiansen
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
mesh_terms: D014150:Antipsychotic Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002746:Chlorpromazine / Q000494:pharmacology; D015169:Colony Count, Microbial; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D016106:Methicillin Resistance / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D010587:Phagocytosis / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D013881:Thioridazine / Q000494:pharmacology*
chemical_list: D014150:Antipsychotic Agents; D013881:Thioridazine; D002746:Chlorpromazine