細菌に薬剤耐性を発現させるメタロ-β-ラクタマーゼの構造機能解析と創薬展開

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  • Structure-Function Analysis and Development of Inhibitors of Metallo-β-lactamases Conferring Drug Resistance in Bacteria
  • サイキン ニ ヤクザイ タイセイ オ ハツゲン サセル メタロ-v-ラクタマーゼ ノ コウゾウ キノウ カイセキ ト ソウヤク テンカイ

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  Metallo-β-lactamases (MBLs) are di-Zn(II) metalloenzymes that efficiently hydrolyze most β-lactam antibiotics used in clinical settings. Bacteria producing MBLs have been isolated from clinical settings and from natural environments such as rivers and soils, and are now recognized as a new potential threat to human health. No effective inhibitors are available for clinical use, making the treatment of infectious diseases caused by bacteria producing MBLs more difficult. IMP-1 is encoded on a plasmid which can be horizontally transferred between bacterial strains. Our studies on MBLs, and especially on IMP-1, focus on understanding the role of Zn(II) ion(s) in the hydrolysis of β-lactam antibiotics and on the detailed structure of the IMP-1 active site in order to develop efficient inhibitors. We investigated the role of the two Zn(II) ions in IMP-1 by kinetic, spectroscopic and thermodynamic analyses. The results revealed that the first Zn(II) ion is necessary for the hydrolysis of β-lactam antibiotics while the second Zn(II) ion enhances enzyme activity and structural stability, thus helping the enzyme achieve maximum activity. The detailed structures of the IMP-1 active site were examined by X-ray crystallography. Thiol compounds for irreversibly inhibiting IMP-1 were developed and the binding mode of these inhibitors was investigated in detail. These findings will aid the design of inhibitors that target MBLs.<br>

収録刊行物

  • 薬学雑誌

    薬学雑誌 135 (11), 1299-1305, 2015-11-01

    公益社団法人 日本薬学会

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