Natural Flavones from Morus alba against Methicillin-Resistant Staphylococcus aureus via Targeting the Proton Motive Force and Membrane Permeability.

The emergence and rapid spread of methicillin-resistant Staphylococcus aureus (MRSA) critically requires alternative therapeutic options. New antibacterial drugs and strategies are urgently needed to combat MRSA-associated infections. Here, we investigated the antibacterial activity of flavones from Morus alba and the potential mode of action against MRSA. Kuwanon G, kuwanon H, mulberrin, and morusin displayed high efficiency in killing diverse MRSA isolates. On the basis of structure-activity analysis, the cyclohexene-phenyl ketones and isopentenyl groups were critical to increase the membrane permeability and to dissipate the proton motive force. Meanwhile, mechanistic studies further showed that kuwanon G displayed rapid bactericidal activity in vitrowith difficulty in developing drug resistance. Kuwanon G targeted phosphatidylglycerol and cardiolipin in the cytoplasmic membrane through the formation of hydrogen bonds and electrostatic interactions. Additionally, kuwanon G promoted wound healing in a mouse model of MRSA skin infection. In summary, these results indicate that flavones are promising lead compounds to treat MRSA-associated infections through disrupting the proton motive force and membrane permeability.

Green tea catechins evoke a phasic contraction in rat aorta via H2O2-mediated multiple-signalling pathways.

1. The contractile effects of tea polyphenols (TP) and its four principle catechins, namely (-)-epicatechin (EC), (-)-epicatechin-3-gallate (ECG), (-)-epigallocatechin (EGC) and (-)-epigallocatechin-3-gallate (EGCG), on rat aorta contractility were investigated using the isometric tension recording technique. 2. At concentrations of 5-100 mg/L, TP evoked phasic contraction of rat aorta in a concentration-dependent but endothelium-independent manner. Of the four catechins tested, EGCG and EGC (3-300 micromol/L), but not EC and ECG, mimicked the contractile response to TP, suggesting that the epigallol moiety in the B ring may be associated with the contractile effect. 3. Contractions in response to EGCG and EGC were not affected by several endogenous vasoconstrictor receptor antagonists, but could be abolished by 10 micro mol/L BAPTA-AM, a membrane-permeable Ca2+ chelator, or attenuated by removal of extracellular Ca2+, suggesting the involvement of both intracellular and extracellular Ca2+ in evoking the contraction. 4. Pretreatment with non-selective Ca2+ channel antagonists mefenamic acid (10 micro mol/L), tetrandrine (30 micro mol/L) and SKF 96365 (30 micromol/L), but not nifedipine (1 micromol/L), the selective inhibitor of voltage-dependent Ca2+ channels, inhibited the contractile responses to EGC and EGCG, indicating the involvement of Ca2+ influx via non-voltage dependent Ca2+ channels. 5. Several intracellular Ca2+ channel modulators, including procaine (5 mmol/L), dantrolene (30 micromol/L) and 2-amino ethoxydiphenyl borate (50 micromol/L; an inositol 1,4,5-trisphosphate receptor inhibitor), also inhibited EGCG- and EGC-induced contractions, thus suggesting a role of intracellular Ca2+ release in these contractions. 6. Both EGCG- and EGC-induced contractions were depressed, to different degrees, by inhibitors of several receptor-coupled enzymes, including phospholipase C, protein kinase C, phospholipase A2 and tyrosine kinase. Furthermore, both EGCG- and EGC-induced contractions were completely abolished by catalase, but not by superoxide dismutase or mannitol/dimethyl sulphoxide. 7. Taken together, these data show, for the first time, that TP and its related catechins that contain an epigallol structure in the B ring, as in EGCG and EGC, exert direct contractile effects on rat aortic smooth muscle via a H2O2-mediated pathway.