title: Rapid bactericidal action of alpha-mangostin against MRSA as an outcome of membrane targeting.
abstract: The emergence of methicillin-resistant Staphylococcus aureus (MRSA) has created the need for better therapeutic options. In this study, five natural xanthones were extracted and purified from the fruit hull of Garcinia mangostana and their antimicrobial properties were investigated. α-Mangostin was identified as the most potent among them against Gram-positive pathogens (MIC=0.78-1.56 μg/mL) which included two MRSA isolates. α-Mangostin also exhibited rapid in vitro bactericidal activity (3-log reduction within 5 min). In a multistep (20 passage) resistance selection study using a MRSA isolated from the eye, no resistance against α-mangostin in the strains tested was observed. Biophysical studies using fluorescence probes for membrane potential and permeability, calcein encapsulated large unilamellar vesicles and scanning electron microscopy showed that α-mangostin rapidly disrupted the integrity of the cytoplasmic membrane leading to loss of intracellular components in a concentration-dependent manner. Molecular dynamic simulations revealed that isoprenyl groups were important to reduce the free energy for the burial of the hydrophobic phenyl ring of α-mangostin into the lipid bilayer of the membrane resulting in membrane breakdown and increased permeability. Thus, we suggest that direct interactions of α-mangostin with the bacterial membrane are responsible for the rapid concentration-dependent membrane disruption and bactericidal action.
authors.affiliation: Singapore Eye Research Institute, 11 Third Hospital Avenue, 168751, Singapore. kohjunjie87@gmail.com
authors.forename: Jun-Jie
authors.initials: JJ
authors.lastname: Koh
authors.forename: Shengxiang
authors.initials: S
authors.lastname: Qiu
authors.forename: Hanxun
authors.initials: H
authors.lastname: Zou
authors.forename: Rajamani
authors.initials: R
authors.lastname: Lakshminarayanan
authors.forename: Jianguo
authors.initials: J
authors.lastname: Li
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zhou
authors.forename: Charles
authors.initials: C
authors.lastname: Tang
authors.forename: Padmanabhan
authors.initials: P
authors.lastname: Saraswathi
authors.forename: Chandra
authors.initials: C
authors.lastname: Verma
authors.forename: Donald T H
authors.initials: DT
authors.lastname: Tan
authors.forename: Ai Ling
authors.initials: AL
authors.lastname: Tan
authors.forename: Shouping
authors.initials: S
authors.lastname: Liu
authors.forename: Roger W
authors.initials: RW
authors.lastname: Beuerman
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001703:Biophysics / Q000379:methods; D002462:Cell Membrane / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004996:Ethidium / Q000494:pharmacology; D005452:Fluoresceins / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D006094:Gram-Positive Bacteria / Q000737:chemistry; D006461:Hemolysis; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D008564:Membrane Potentials; D055624:Methicillin-Resistant Staphylococcus aureus / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D008855:Microscopy, Electron, Scanning / Q000379:methods; D008956:Models, Chemical; D009930:Organic Chemicals / Q000494:pharmacology; D010539:Permeability; D011817:Rabbits; D013997:Time Factors; D044004:Xanthones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D005452:Fluoresceins; D005456:Fluorescent Dyes; D009930:Organic Chemicals; C402795:SYTOX Green; D044004:Xanthones; D004996:Ethidium; C021053:mangostin; C007740:fluorexon