The Institute of Scientific and Industrial Research, Osaka University


LAST UPDATE 2017/02/26

  • 研究者氏名
    Researcher Name

    山崎聖司 Seiji YAMASAKI
    准教授 Associate Professor
  • 所属
    Professional Affiliation

    The Institute of Scientific and Industrial Research, Osaka University

    Department of Biomolecular Science and Regulation
  • 研究キーワード
    Research Keywords

    Membrane transporters
    Multidrug resistance
    Infectious diseases
Research Subject
Drug development against resistant bacterial infections using the structural-functional information of multidrug efflux pumps

研究の背景 Background


The multidrug efflux pumps are important in the bacterial multidrug resistance. However, clinically useful inhibitors are not available at present. We have previously revealed that drugs were shown to be exported by a functionally rotating mechanism (Nature, 2006) through tandem proximal and distal multisite drug-binding pockets (Nature, 2011), and the sensitivity of pumps to inhibitor depended on the space of the inhibitor-binding pit (Nature, 2013). It's expected that these structural-functional informations will contribute to the development of new medicines.

研究の目標 Outcome


We are aiming to develop new medicines or strategies against resistant bacterial infections by understanding the drug resistance mechanism. Now we are trying to develop novel efflux pump inhibitors. Actually, on the basis of the structural-functional information obtained previously, we found some new medicine candidate compounds. They have the possibilities of becoming good clinically useful inhibitors.

研究図Research Figure

Fig.1. Comparison of the inhibitor-binding pit of multidrug efflux pumps. The presence of a voluminous amino acid residue at the middle of inhibitor-binding pit reduces the inhibitory activity of pump inhibitor. Fig.2. LC-MS/MS efflux assay. In the case of pump-expressing cells and substrate drug, the drug concentration in the medium shows no change because the active efflux prevents drug accumulation in bacterial cells. Fig.3. Evaluation of the putative ABI-PP-bound structures. The sensitivity of pumps to pump inhibitor depends on the space of the inhibitor-binding pit.

文献 / Publications

山崎聖司, 西野邦彦, 薬剤排出トランスポーターの分子生物学, 化学療法の領域, (株)医薬ジャーナル社 (2015). Int. J. Antimicrob. Agents 45, 439 (2015).
Nature 500, 102 (2013). J. Antimicrob. Chemother. 68, 1066 (2013), 66, 291 (2011), 65, 853 (2010). Nature 480, 565 (2011). J. Antibiot. 64, 433 (2011).