Molecular mechanisms of thioridazine resistance in Staphylococcus aureus

Autor: Mette Thorsing, Sabrina Prehn Lauritzen, Lars Christian Lund, Claes Søndergaard Wassmann, Janne Kudsk Klitgaard, Birgitte H. Kallipolitis, Hans Jørn Kolmos
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
Physiology
Staphylococcus
Mutagenesis and Gene Deletion Techniques
Antibiotics
lcsh:Medicine
Transferases (Other Substituted Phosphate Groups)
Membrane Potentials/drug effects
Thioridazine
medicine.disease_cause
Pathology and Laboratory Medicine
Membrane Potentials
chemistry.chemical_compound
Cardiolipin
Medicine and Health Sciences
Dicloxacillin
Staphylococcus Aureus
Thioridazine/pharmacology
lcsh:Science
Phylogeny
Methicillin-Resistant Staphylococcus aureus/drug effects
Multidisciplinary
Chemistry
Antimicrobials
Drugs
Drug Resistance
Bacterial/genetics
Bacterial Pathogens
Anti-Bacterial Agents
Electrophysiology
Staphylococcus aureus
Medical Microbiology
medicine.symptom
Pathogens
medicine.drug
Research Article
Methicillin-Resistant Staphylococcus aureus
medicine.drug_class
Cardiolipins
Dicloxacillin/pharmacology
030106 microbiology
Microbial Sensitivity Tests
Research and Analysis Methods
Membrane Potential
Microbiology
Anti-Bacterial Agents/pharmacology
03 medical and health sciences
Antibiotic resistance
Bacterial Proteins
Microbial Control
Drug Resistance
Bacterial
medicine
Genetics
Membrane Proteins/genetics
Cardiolipins/metabolism
Molecular Biology Techniques
Microbial Pathogens
Molecular Biology
Pharmacology
Transferases (Other Substituted Phosphate Groups)/genetics
Bacteria
Whole Genome Sequencing
Bacterial Proteins/genetics
lcsh:R
Deletion Mutagenesis
Organisms
Biology and Life Sciences
Membrane Proteins
Methicillin-resistant Staphylococcus aureus
Mechanism of action
Antibiotic Resistance
Mutation
lcsh:Q
Antimicrobial Resistance
Zdroj: PLoS ONE
PLoS ONE, Vol 13, Iss 8, p e0201767 (2018)
Wassmann, C S, Lund, L C, Thorsing, M, Prehn Lauritzen, S, Kolmos, H J, Kallipolitis, B H & Klitgaard, J K 2018, ' Molecular mechanisms of thioridazine resistance in Staphylococcus aureus ', P L o S One, vol. 13, no. 8, e0201767, pp. 1-17 . https://doi.org/10.1371/journal.pone.0201767
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0201767
Popis: 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.
Databáze: OpenAIRE
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