title: Synergistic effects of diosmetin with erythromycin against ABC transporter over-expressed methicillin-resistant Staphylococcus aureus (MRSA) RN4220/pUL5054 and inhibition of MRSA pyruvate kinase.
abstract: Increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) worldwide with limited therapeutic options is a growing public health concern. Natural products have been shown to possess antibacterial actions against MRSA. Flavonoids from natural products have been shown to possess antibacterial actions against MRSA by antagonizing its resistance mechanisms. Diosmin and diosmetin are natural flavonoids found in a variety of citrus fruits. The aim of this study was to investigate whether diosmin and diosmetin could inhibit the growth of MRSA and the in vitro enzymatic activity of a newly discovered MRSA drug target, pyruvate kinase (PK). By using a panel of MRSA strains with known resistant mechanisms, neither diosmin nor diosmetin was shown to possess direct antibacterial activities against all tested MRSA strains. However, in checkerboard assay, we found that diosmetin together with erythromycin, could synergistically inhibit the growth of ABC-pump overexpressed MRSA-RN4220/pUL5054, and time kill assay also showed that the antibacterial activities of diosmetin with erythromycin were bactericidal. Diosmetin was further shown to significantly suppress the MRSA PK activities in a dose dependent manner. In conclusion, the inhibition of MRSA PK by diosmetin could lead to a deficiency of ATP and affect the bacterial efflux pump which might contribute to the antibacterial actions of diosmetin against MRSA.
authors.affiliation: Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
authors.forename: Ben C L
authors.initials: BC
authors.lastname: Chan
authors.forename: Margaret
authors.initials: M
authors.lastname: Ip
authors.forename: H
authors.initials: H
authors.lastname: Gong
authors.forename: S L
authors.initials: SL
authors.lastname: Lui
authors.forename: Raymond H
authors.initials: RH
authors.lastname: See
authors.forename: Claude
authors.initials: C
authors.lastname: Jolivalt
authors.forename: K P
authors.initials: KP
authors.lastname: Fung
authors.forename: P C
authors.initials: PC
authors.lastname: Leung
authors.forename: Neil E
authors.initials: NE
authors.lastname: Reiner
authors.forename: Clara B S
authors.initials: CB
authors.lastname: Lau
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004145:Diosmin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004917:Erythromycin / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D011770:Pyruvate Kinase / Q000037:antagonists & inhibitors*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D005419:Flavonoids; D004917:Erythromycin; D004145:Diosmin; D000255:Adenosine Triphosphate; D011770:Pyruvate Kinase; C039602:diosmetin