The genus Terminalia has a long history of use in traditional medicine to treat various diseases, including bacterial infections. We previously reported a metabolomic analysis using liquid chromatography-mass spectrometry of selected Australian Terminalia spp. and highlighted numerous flavonoids that may contribute to the antimicrobial activities of those plants. This study examines the antibacterial activities of fifteen flavonoids found in Terminalia spp. against a range of gastrointestinal pathogens using broth dilution assays. Flavonoids were also combined with six different classes of conventional antibiotics to investigate interactions. The efflux pump inhibitory activity of the flavonoid was evaluated using ethidium bromide accumulation and efflux assays. Toxicities were assessed via human dermal fibroblast cell line assays. Fisetin, hispidulin, isoorientin, orientin, rutin, and vitexin showed noteworthy growth inhibitory activity (MIC values 62.5-250 µg/mL). Isoorientin and orientin were most potent against Bacillus cereus and Alcaligenes faecalis, displaying MIC values of 62.5 µg/mL against both bacteria. All flavonoids except genistein, isorhamnetin, kaempferol, luteolin, taxifolin, and vitexin were nontoxic in human dermal fibroblast (HDF) cell proliferation assays. When individual flavonoids were combined with selected antibiotics, some potentiated the activity of these antibiotics. Two synergistic, eighteen additive and thirty-one non-interactive interactions were observed. The synergistic interactions were all observed in combination with orientin. Notably, orientin exhibited efflux pump inhibitory effects at concentrations from 15.26 µg/mL to 125 µg/mL. The findings reported herein indicate that the selected flavonoids have the potential for addressing bacterial antibiotic resistance and highlight the need for further study.

With the diet, we ingest nutrients capable of modulating platelet function, which plays a crucial role in developing cardiovascular events, one of the leading causes of mortality worldwide. Studies that demonstrate the antiplatelet and antithrombotic potential of bioactive compounds are vital to maintaining good cardiovascular health. In this work, we evaluate the flavonol isorhamnetin's antiplatelet effect on human platelets, using collagen, thrombin receptor activator peptide 6 (TRAP-6), and phorbol myristate acetate (PMA) as agonists. Isorhamnetin induced a significant inhibition on collagen- and TRAP-6-induced platelet aggregation, with half-maximum inhibitory concentration (IC50) values of 8.1 ± 2.6 and 16.1 ± 11.1 µM, respectively; while it did not show cytotoxic effect. Isorhamnetin reduced adenosine triphosphate levels (ATP) in platelets stimulated by collagen and TRAP-6. We also evidenced that isorhamnetin's antiplatelet activity was related to the inhibition of mitochondrial function without effect on reactive oxygen species (ROS) levels. Additionally, we investigated isorhamnetin's effect on thrombus formation in vitro under flow conditions on the damaged vessel wall. In this context, we demonstrate that isorhamnetin at 20 µM induced a significant inhibition on platelet deposition, confirming its antithrombotic effect. Our findings corroborate the antiplatelet and antithrombotic potential of isorhamnetin present in many foods of daily consumption.