ArticlePloS one2018
Molecular mechanisms of thioridazine resistance in Staphylococcus aureus.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Case report: Methicillin-resistantFrontiers in medicine · 2024Article
- Pleiotropic actions of phenothiazine drugs are detrimental to Gram-negative bacterial persister cells.Communications biology · 2022Article
- β-Lactams against the Fortress of the Gram-PositiveChemical reviews · 2021Review
- Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration.Frontiers in microbiology · 2021Article
- Anti-staphylococcal activity and mode of action of thioridazine photoproducts.Scientific reports · 2020Article
- Inhibition of Fatty Acid Oxidation as a New Target To Treat Primary Amoebic Meningoencephalitis.Antimicrobial agents and chemotherapy · 2020Article
- A Novel Promazine Derivative Shows HighFrontiers in microbiology · 2020Article
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Authors and funding
7 authors.
Funding
No grant is acknowledged in the PubMed record.
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.
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