Thioridazine Applications in Antimicrobial Resistance
Summary
Thioridazine, a phenothiazine derivative historically deployed as an antipsychotic, has gained considerable attention as a helper compound to combat antimicrobial resistance. Beyond its central nervous system effects, it exhibits intrinsic activity against Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Its multifunctional mechanisms encompass inhibition of bacterial efflux pumps, disruption of membrane potential and interference with peptidoglycan assembly, thereby restoring or enhancing the efficacy of β-lactam antibiotics. Innovations in the field include the design of thioridazine derivatives with reduced neurotoxicity and the generation of photoproducts via laser irradiation to amplify antibacterial potency. While systemic use is constrained by dose-related side effects, topical or targeted applications and combination therapies underscore thioridazine’s continuing relevance in extending the repertoire of existing antimicrobials.
Research from Nature Portfolio
Recent studies have demonstrated that laser-irradiated thioridazine solutions yield photoproducts with significantly enhanced activity against Gram-positive bacteria, surpassing conventional agents in potency against methicillin- and ciprofloxacin-resistant Staphylococcus aureus. Spectroscopic and chromatographic analyses have characterised these photoproducts, and molecular docking suggests they bind with higher affinity to penicillin-binding proteins such as PBP2a. This work underscores a cost-effective photochemical approach to repurpose an existing drug scaffold into a potent anti-MRSA strategy without necessitating extensive chemical synthesis.
Thioridazine Applications in Antimicrobial Resistance publication trend
The graph below shows the total number of articles in thioridazine applications in antimicrobial resistance across all publications each year (not limited to Nature Index journals).
Technical terms
Phenothiazine: A chemical class of compounds originally developed as antipsychotics, some of which exhibit antibacterial properties.
Minimum Inhibitory Concentration (MIC): The lowest concentration of an antimicrobial agent required to prevent visible growth of a microorganism in vitro.
Efflux pump: A membrane-embedded protein complex that expels toxic substances, including antibiotics, from bacterial cells, contributing to resistance.
Peptidoglycan: A polymeric mesh of sugars and amino acids forming the bacterial cell wall, essential for cell shape and integrity.
Penicillin-binding protein (PBP): Enzymes that catalyse the final cross-linking steps of peptidoglycan synthesis and serve as targets for β-lactam antibiotics.
References
- Anti-staphylococcal activity and mode of action of thioridazine photoproducts. Scientific Reports (2020).
- Thioridazine Induces Major Changes in Global Gene Expression and Cell Wall Composition in Methicillin-Resistant Staphylococcus aureus USA300. PLOS ONE (2013).
- Molecular mechanisms of thioridazine resistance in Staphylococcus aureus. PLOS ONE (2018).
- A Novel Derivative of Thioridazine Shows Low Toxicity and Efficient Activity against Gram-Positive Pathogens. Antibiotics (2020).
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