Antibiotic resistance became an increasing risk for population health threatening our ability to fight infectious diseases. The objective of this study was to evaluate the activity of laser irradiated thioridazine (TZ) against clinically-relevant bacteria in view to fight antibiotic resistance. TZ in ultrapure water solutions was irradiated (1–240 min) with 266 nm pulsed laser radiation. Irradiated solutions were characterized by UV–Vis and FTIR absorption spectroscopy, thin layer chromatography, laser-induced fluorescence, and dynamic surface tension measurements. Molecular docking studies were made to evaluate the molecular mechanisms of photoproducts action against Staphylococcus aureus and MRSA. More general, solutions were evaluated for their antimicrobial and efflux inhibitory activity against a panel of bacteria of clinical relevance. We observed an enhanced antimicrobial activity of TZ photoproducts against Gram-positive bacteria. This was higher than ciprofloxacin effects for methicillin- and ciprofloxacin-resistant Staphylococcus aureus. Molecular docking showed the Penicillin-binding proteins PBP3 and PBP2a inhibition by sulforidazine as a possible mechanism of action against Staphylococcus aureus and MRSA strains, respectively. Irradiated TZ reveals possible advantages in the treatment of infectious diseases produced by antibiotic-resistant Gram-positive bacteria. TZ repurposing and its photoproducts, obtained by laser irradiation, show accelerated and low-costs of development if compared to chemical synthesis.
The worldwide infection with the new Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) demands urgently new potent treatment(s). In this study we predict, using molecular docking, the binding affinity of 15 phenothiazines (antihistaminic and antipsychotic drugs) when interacting with the main protease (M pro ) of SARS-CoV-2. Additionally, we tested the binding affinity of photoproducts identified after irradiation of phenothiazines with Nd:YAG laser beam at 266 nm respectively 355 nm. Our results reveal that thioridazine and its identified photoproducts (mesoridazine and sulforidazine) have high biological activity on the virus M pro . This shows that thioridazine and its two photoproducts might represent new potent medicines to be used for treatment in this outbreak. Such results recommend these medicines for further tests on cell cultures infected with SARS-CoV-2 or animal model. The transition to human subjects of the suggested treatment will be smooth due to the fact that the drugs are already available on the market.
Antidepressants and antipsychotics are drugs used in the treatment of neuropsychiatric disorders, but because they have side effects on new-borns their use is not recommended during pregnancy. Natural compounds represent an innovative opportunity for the management of depression, but the molecular mechanisms on brain membrane receptors are unknown. Our aims are to predict the binding affinities of melatonin, resveratrol, linalool and linalyl acetate at SERT (serotonin transporter), deeply involved in neuropsychiatric disorders mechanisms, their drug likeness, pharmacokinetics features and the transfer index (TI) through placenta by using QSAR (Quantitative Structure-Activity Relationship) and in silico ADMET (Absorption Distribution Metabolism Excretion Toxicity) techniques. Our study concluded that natural compounds represent promising drug candidates in the treatment of depression. RezumatAntidepresivele și antipsihoticele sunt medicamente utilizate în tratamentul patologiilor neuropsihiatrice, dar din cauza efectelor negative asupra nou-născuților, acestea nu sunt recomandate utilizării pe parcursul sarcinii. Compușii naturali reprezintă o alternativă promițătoare în tratamentul depresiei, dar mecanismul molecular al acestora asupra receptorilor membranari din creier este necunoscut. Scopul acestui studiu este de a evalua activitatea biologică a melatoninei, resveratrolului, acetatului de linalil și linalol asupra transportorului de serotonina (implicat în mecanismul patologiilor psihiatrice), caracterul de medicament, caracteristicile farmacocinetice și indicele de transfer (IT) placentar, utilizând tehnicile QSAR și ADMET in silico. Acest studiu a arătat că acești compuși naturali reprezintă candidați promițători pentru tratamentul depresiei.
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