title: Thioridazine Alters the Cell-Envelope Permeability of Mycobacterium tuberculosis.
abstract: The increasing occurrence of multidrug resistant tuberculosis exerts a major burden on treatment of this infectious disease. Thioridazine, previously used as a neuroleptic, is active against extensively drug resistant tuberculosis when added to other second- and third-line antibiotics. By quantitatively studying the proteome of thioridazine-treated Mycobacterium tuberculosis, we discovered the differential abundance of several proteins that are involved in the maintenance of the cell-envelope permeability barrier. By assessing the accumulation of fluorescent dyes in mycobacterial cells over time, we demonstrate that long-term drug exposure of M. tuberculosis indeed increased the cell-envelope permeability. The results of the current study demonstrate that thioridazine induced an increase in cell-envelope permeability and thereby the enhanced uptake of compounds. These results serve as a novel explanation to the previously reported synergistic effects between thioridazine and other antituberculosis drugs. This new insight in the working mechanism of this antituberculosis compound could open novel perspectives of future drug-administration regimens in combinational therapy.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre (LUMC) , Leiden, 2300 RC The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Keijzer
authors.forename: Arnout
authors.initials: A
authors.lastname: Mulder
authors.forename: Petra E W
authors.initials: PE
authors.lastname: de Haas
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre (LUMC) , Leiden, 2300 RC The Netherlands.
authors.forename: Arnoud H
authors.initials: AH
authors.lastname: de Ru
authors.forename: Evy M
authors.initials: EM
authors.lastname: Heerkens
authors.affiliation: Travel Medicine of the CMDT, Institute of Hygiene and Tropical Medicine, Universidade Nova de Lisboa , Lisboa, 1349-008 Portugal.
authors.forename: Leonard
authors.initials: L
authors.lastname: Amaral
authors.affiliation: Departments of Pulmonary Diseases and Medical Microbiology, Radboud University Medical Centre , Nijmegen, 6500 HB The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: van Soolingen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Centre (LUMC) , Leiden, 2300 RC The Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
mesh_terms: D002463:Cell Membrane Permeability / Q000187:drug effects*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000648:ultrastructure; D020543:Proteome / Q000187:drug effects*; D013881:Thioridazine / Q000494:pharmacology*
chemical_list: D020543:Proteome; D013881:Thioridazine
keywords: Mycobacterium tuberculosis; cell envelope; permeability; quantitative proteomics; thioridazine