Molecular mechanisms of thioridazine resistance in Staphylococcus aureus

Claes Søndergaard Wassmann, Lars Christian Lund, Mette Thorsing, Sabrina Prehn Lauritzen, Hans Jørn Kolmos, Birgitte H. Kallipolitis, Janne Kudsk Klitgaard*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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Abstract

Staphylococcus aureus has developed resistance towards the most commonly used anti-staphylococcal antibiotics. Therefore, there is an urgent need to find new treatment opportunities. A new approach relies on the use of helper compounds, which are able to potentiate the effect of antibiotics. A well-studied helper compound is thioridazine, which potentiates the effect of the β-lactam antibiotic dicloxacillin against Methicillin-resistant Staphylococcus aureus (MRSA). In order to identify thioridazine’s mechanism of action and how it potentiates the effect of dicloxacillin, we generated thioridazine resistant strains of MRSA USA300 by serial passage experiments. Selected strains were whole-genome sequenced to find mutations causing thioridazine resistance. Genes observed to be mutated were attempted deleted in MRSA USA300. The cls gene encoding a cardiolipin synthase important for synthesis of the membrane lipid cardiolipin was found to be mutated in thioridazine resistant strains. Deletion of this gene resulted in a two-fold increased Minimum inhibitory concentrations (MIC) value for thioridazine compared to the wild type and decreased susceptibility similar to the thioridazine resistant strains. Since cardiolipin likely plays a role in resistance towards thioridazine, it might also be important for the mechanism of action behind the potentiating effect of thioridazine. TDZ is known to intercalate into the membrane and we show here that TDZ can depolarize the plasma membrane. However, our results indicate that the membrane potential reducing effect of TDZ is independent of the resistance mechanism.
Original languageEnglish
Article numbere0201767
JournalP L o S One
Volume13
Issue number8
Pages (from-to)1-17
ISSN1932-6203
DOIs
Publication statusPublished - 8. Aug 2018

Keywords

  • Anti-Bacterial Agents/pharmacology
  • Bacterial Proteins/genetics
  • Cardiolipins/metabolism
  • Dicloxacillin/pharmacology
  • Drug Resistance, Bacterial/genetics
  • Membrane Potentials/drug effects
  • Membrane Proteins/genetics
  • Methicillin-Resistant Staphylococcus aureus/drug effects
  • Microbial Sensitivity Tests
  • Mutation
  • Phylogeny
  • Thioridazine/pharmacology
  • Transferases (Other Substituted Phosphate Groups)/genetics
  • Whole Genome Sequencing

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