2003 Fiscal Year Final Research Report Summary
TITLE OF PROJECT : Invention of intensifiers of antibiotics-susceptibility against multi-drugs resistant pathogenic bacteria and invesrigation for novel control system of multi-drugs resistance
| Project/Area Number |
14390038
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
広領域
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| Research Institution | The University of Tokushima |
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Principal Investigator |
HIGUTI Tomihiko The University of Tokushima, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (50035557)
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| Co-Investigator(Kenkyū-buntansha) |
SHIKISHIMA Yasuhiro Alps Pharmaceutical Industries, Co. Ltd., Division of Developmental Research, Researcher, 開発部, 研究員
SHIBATA Hirofumi The University of Tokushima, Faculty of Pharmaceutical Sciences, Research Associate, 薬学部, 助手 (00093865)
ARAKAKI Naokatu The University of Tokushima, Faculty of Pharmaceutical Sciences, Associate Professor, 薬学部, 助教授 (60151148)
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| Project Period (FY) |
2002 – 2003
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| Keywords | medicinal plants / MRSA / intensifier of β-lactam-susceptibility / high throughput screening / alkyl gallate / structure-activity relationship / flavone / two-components signal transduction system |
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| Research Abstract |
High-throughput screening for novel intensifiers of β-lactam-susceptibility in MRSAs (ILSMRs)
We were screening for the activity of 900 species of medicinal plants to modulate β-lactam resistance of methicillin-resistant Staphylococcus aureus (MRSA). We found 43 species of plants which showed the potent antibacaterial activity and the same number of plants which had the ILSMR activity. Among them, a methanol extract of fruit pods of Caesalpinia spinosa (Tara) showed a potent ILSMR activity. By the activity-guided fractionation of the extracts, we purified and identified four compounds including ethyl gallate as effective constituents. SAR analysis with various alkyl gallates and the related compounds revealed the significant contribution of the galloyl moiety and the alkyl chain. The optimum alkyl chain lengths were shown at C9-10 for the antibacterial activity and at C5-6 for the ILSMR activity
We also found that Bergenia purpurascens (Gan-hakusai) showed remarkable activity. The isolation and identification procedure of active principles from the fraction is in progress
Study on the mechanism of action of novel ILSMRs
We detected 16 up-regulated clones, including the genes associated with fatty acid metabolism and those encoding the two-component signal transduction system (TCSTS), and 10 down-regulated clones, including the genes associated with metabolic pathways such as the tricarboxylic acid cycle and oxidative phosphorylation. A positive correlation was found between the up-regulation of the TCSTS and the β-lactam susceptibility intensified by flavone in the MRSA strains, and disruption of the gene encoding the sensor of the TCSTS resulted in decreased oxacillin resistance. The results suggest important roles of the TCSTS in resistance to β-lactam antibiotics
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