MIC values for unirradiated and irradiated TZ were 100В mg/L for E. aureus/MRSA cell wall biosynthesis and cell division.ДЇor Gram-negative bacteria, irradiated TZ had no enhanced antimicrobial effect when compared to unirradiated TZ. Possible mechanisms of action of TZ and its photoproducts were identified using several molecular docking models on three membrane proteins involved in S. Drug-likeness of the suggested photoproducts was evaluated by applying drug-like rules such as LipinskiвЂ™s rule of five and Veber bioavailability rule. We characterized irradiated TZ to evidence its photodegradation and generation of photoproducts. Our study is focused on TZ repurposing from an anti-psychosis drug to an antimicrobial one, by irradiating it with 266В nm pulsed laser radiation to obtain an enhanced antimicrobial effect against multiple drug-resistant (MDR) bacteria. Therefore, TZ could be considered a multi-purpose drug that could be repurposed as an antimicrobial agent. Moreover, other groups considered using TZ as anti-tuberculosis 8, 9, anti-inflammatory 10, or anti-tumoral 11 drug. Thanacoody mentioned that TZ inactive metabolites or its enantiomers may have a future in development of antimicrobial drugs efficient in challenging infectious diseases 7. aureus) strains resistant to it by increased efflux, indicating a TZ role as an efflux inhibitor 5, as is the case also for Proteus mirabilis 6. demonstrated that TZ can reduce the minimum inhibitory concentration (MIC) of ciprofloxacin (CIP) in Staphylococcus aureus ( S. observed that TZ presents antimicrobial activity against 316В Gram-positive and Gram-negative bacterial strains 4. So, several groups have investigated the possibility of using thioridazine (TZ) as an antimicrobial agent. This is the case of phenothiazines in fighting infectious diseases acquired by multiple drug resistance (MDR) mechanisms. There are several approaches currently used in drug discovery 1, 2, 3 that can help pharmaceutical progress, one of them being drug repurposing 1, 2, 3 which basically consists of using drugs designed and approved to treat other diseases than their initial target. New low-cost drugs are needed, that are conceived for higher efficacy treatment and are suitable to be faster introduced in production phase. Nowadays, due to this already worldwide problem, drug discovery for treatment of such infections is approached with increasing attention. TZ repurposing and its photoproducts, obtained by laser irradiation, show accelerated and low-costs of development if compared to chemical synthesis.ДЄntimicrobial resistance is an increasing major risk to population health threatening our ability to fight infectious diseases. Irradiated TZ reveals possible advantages in the treatment of infectious diseases produced by antibiotic-resistant Gram-positive bacteria. 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. This was higher than ciprofloxacin effects for methicillin- and ciprofloxacin-resistant Staphylococcus aureus.

We observed an enhanced antimicrobial activity of TZ photoproducts against Gram-positive bacteria. More general, solutions were evaluated for their antimicrobial and efflux inhibitory activity against a panel of bacteria of clinical relevance. Molecular docking studies were made to evaluate the molecular mechanisms of photoproducts action against Staphylococcus aureus and MRSA. Irradiated solutions were characterized by UVвЂ“Vis and FTIR absorption spectroscopy, thin layer chromatography, laser-induced fluorescence, and dynamic surface tension measurements. TZ in ultrapure water solutions was irradiated (1вЂ“240В min) with 266В nm pulsed laser radiation. 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.

Antibiotic resistance became an increasing risk for population health threatening our ability to fight infectious diseases.

Pbp3 resistance