Unlocking bacterial defense: Exploring the potent inhibition of NorA efflux pump by coumarin derivatives in Staphylococcus aureus.

The occurrence of bacterial resistance has been increasing, compromising the treatment of various infections. The high virulence of Staphylococcus aureus allows for the maintenance of the infectious process, causing many deaths and hospitalizations. The MepA and NorA efflux pumps are transporter proteins responsible for expelling antimicrobial agents such as fluoroquinolones from the bacterial cell. Coumarins are phenolic compounds that have been studied for their diverse biological actions, including against bacteria. A pharmacokinetic in silico characterization of compounds C10, C11, C13, and C14 was carried out according to the principles of Lipinski's Rule of Five, in addition to searching for similarity in ChemBL and subsequent search for publications in CAS SciFinder. All compounds were evaluated for their in vitro antibacterial and modulatory activity against standard and multidrug-resistant Gram-positive and Gram-negative strains. The effect of coumarins C9, C10, C11, C13, and C14 as efflux pump inhibitors in Staphylococcus aureus strains was evaluated using the microdilution method (MepA or NorA) and fluorimetry (NorA). The behavior of coumarins regarding the efflux pump was determined from their interaction properties with the membrane and coumarin-protein using molecular docking and molecular dynamics simulations. Only the isolated coumarin compound C13 showed antibacterial activity against standard strains of Staphylococcus aureus and Escherichia coli. However, the other tested coumarins showed modulatory capacity for fluoroquinolone and aminoglycoside antibacterials. Compounds C10, C13, and C14 were effective in reducing the MIC of both antibiotics for both multidrug-resistant strains, while C11 potentiated the effect of norfloxacin and gentamicin for Gram-positive and Gram-negative bacteria and only norfloxacin for Gram-negative. Only coumarin C14 produced synergistic effects when associated with ciprofloxacin in MepA-carrying strains. All tested coumarins have the ability to inhibit the NorA efflux pump present in Staphylococcus aureus, both in reducing the MIC and inducing increased ethidium bromide fluorescence emission in fluorimetry. The findings of this study offer an atomistic perspective on the potential of coumarins as active inhibitors of the NorA pump, highlighting their specific mode of action mainly targeting protein inhibition. In molecular docking, it was observed that coumarins are capable of interacting with various amino acid residues of the NorA pump. The simulation showed that coumarin C10 can cross the bilayer; however, the other coumarins interacted with the membrane but were unable to cross it. Coumarins demonstrated their potentiating role in the effect of norfloxacin through a dual mechanism: efflux pump inhibition through direct interaction with the protein (C9, C10, C11, and C13) and increased interaction with the membrane (C10 and C13). In the context of pharmacokinetic prediction studies, the studied structures have a suitable chemical profile for possible oral use. We suggest that coumarin derivatives may be an interesting alternative in the future for the treatment of resistant bacterial infections, with the possibility of a synergistic effect with other antibacterials, although further studies are needed to characterize their therapeutic effects and toxicity.

Anti-inflammatory activities of the hydroalcoholic extracts from Erythrina velutina and E. mulungu in mice

This work studied the anti-inflammatory activities of the hydroalcoholic extracts (HAEs) from Erythrina velutina Willd. (Ev) and E. mulungu Mart. ex Benth. (Em) in the carrageenan- and dextran-induced mice hind paw edema models. These medicinal plants belonging to the Fabaceae family are used in some Brazilian communities to treat pain, inflammation, insomnia and disorders of the central nervous system. In the present work, the extracts were administered orally in male mice at the doses of 200 or 400 mg/kg. In the carrageenan-induced test, only Em showed anti-inflammatory activity, decreasing the paw edema, at the doses of 200 and 400 mg/kg. No effect was observed with Ev in this model. On the other hand, in the dextran model, Ev demonstrated anti-inflammatory effect, showing decrease of the paw edema at the 1, 2, 3, 4 and 24th h. Em (200 or 400 mg/kg) presented anti-inflammatory effect at the 2, 3 and 4th h after administration of dextran, as compared to control. In conclusion, the work showed that Ev and Em present anti-edematous actions, which possibly occurs by distinct mechanisms. While Ev seems to interfere especially in inflammatory processes in which mast cells have an important role, Em exerts greater activity in the inflammatory process that depends mainly on polymorphonuclear leucocytes. However, further studies are needed to determine the exact mechanism of action of the species investigated.

Plantas medicinais e seus constituintes bioativos: uma revisão da bioatividade e potenciais benefícios nos distúrbios da ansiedade em modelos animais: [revisão] / Medicinal plants and their bioactive constituents: a scientific review of bioactivity and potential benefits in the anxiety disorders in animal models: [revision]

A procura de novos agentes terapêuticos provenientes de plantas medicinais para doenças psiquiátricas tem progredido significativamente na última década. Isso reflete num grande número de preparações herbárias para as quais o potencial psicoterapêutico tem sido avaliado em diversos modelos animais. O intuito desta revisão é fornecer uma ampla visão das plantas medicinais que apresentam efeitos terapêuticos significantes em modelos animais de doenças psiquiátricas, especificamente os distúrbios da ansiedade. Um considerável número de constituintes herbários cujos efeitos comportamentais e ações farmacológicas têm sido bem caracterizados podem ser bons candidatos para futuras investigações que podem resultar em uso clínico, merecendo, portanto, uma maior atenção em estudos posteriores.

A search for novel pharmacotherapy from medicinal plants for psychiatric illnesses has progressed significantly in the past decade. This is reflected in the large number of herbal preparations for which psychotherapeutic potential has been evaluated in a variety of animal models. The aim of this review is to provide an overview of medicinal plants that have significant therapeutic effects in animal models of psychiatric illnesses, specifically anxiety disorders. A considerable number of herbal constituents whose behavioral effects and pharmacological actions have been well characterized may be good candidates for future investigations that may result in clinical use, thus deserving increased attention in future studies.