Abstract
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.
Highlights
Antibiotic resistance became an increasing risk for population health threatening our ability to fight infectious diseases
TZ irradiated 120 min showed consistently the best antimicrobial effect across all tested strains, showing minimum inhibitory concentration (MIC) values four-fold to 16-fold lower than for unirradiated TZ. This enhanced antimicrobial activity was more pronounced for S. aureus, including the ciprofloxacin-resistant strains, due to increased efflux (S. aureus ATCC 25923 EtBr) or mutations in the target proteins (S. aureus SM1)
Developing new antimicrobial agents by the repurposing of current non-antibiotics could have a major benefit in allowing the extended reuse of existing medicines
Summary
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. 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. Antimicrobial resistance is an increasing major risk to population health threatening our ability to fight infectious diseases Nowadays, due to this already worldwide problem, drug discovery for treatment of such infections is approached with increasing attention. There are several approaches currently used in drug discovery that can help pharmaceutical progress, one of them being drug repurposing which basically consists of using drugs designed and approved to treat other diseases than their initial target This is the case of phenothiazines in fighting infectious diseases acquired by multiple drug resistance (MDR) mechanisms. Possible mechanisms of action of TZ and its photoproducts were identified using several molecular docking models on three membrane proteins involved in S. aureus/MRSA cell wall biosynthesis and cell division
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