Rapid bactericidal action of alpha-mangostin against MRSA as an outcome of membrane targeting |
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Authors: | Jun-Jie Koh Shengxiang Qiu Hanxun Zou Rajamani Lakshminarayanan Jianguo Li Xiaojun Zhou Charles Tang Padmanabhan Saraswathi Chandra Verma Donald TH Tan Ai Ling Tan Shouping Liu Roger W Beuerman |
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Institution: | 1. Singapore Eye Research Institute, 11 Third Hospital Avenue, 168751, Singapore;2. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 119074, Singapore;3. Program for Natural Products Medicinal Chemistry & Drug Discovery, Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, the Chinese Academy of Sciences, Guangzhou, China;4. Bioinformatics Institute (A*STAR), 30 Biopolis Street, 07-01 Matrix, 138671, Singapore;5. Pharmaceutical Microbiology Laboratory, Department of Pathology, Singapore General Hospital, 169608, Singapore;6. Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, 117543, Singapore;7. School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, 637551, Singapore;8. Singapore National Eye Center, 168751, Singapore;9. Department of Pathology, Singapore General Hospital, 169608, Singapore;10. Duke-NUS Medical School, SRP Neuroscience and Behavioural Division, 169857, Singapore |
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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. |
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