“细菌多药物外输转运物”的抑制剂是克服细菌“多药物抗性”所必需的，但目前还没有在临床上有用的抑制剂。“多药物外输转运物”AcrB及其同系物促进很多革兰氏阴性病原体的“多药物抗性”，Akihito Yamaguchi及其同事在这篇论文中首次描述了与抑制剂结合在一起的AcrB及其同系物MexB的X-射线晶体结构。该抑制剂（一种“吡啶并嘧啶”衍生物）在一个窄的憎水“坑”中结合，抑制AcrB/MexB单体的功能性旋转。这些与抑制剂结合在一起的结构也许能促进这一家族的“多药物外输转运物”的新抑制剂的开发，后者可与现有抗生素一起使用，以使其疗效更好。（生物谷 Bioon.com）
生物谷推荐的英文摘要
Nature doi:10.1038/nature12300
Structural basis for the inhibition of bacterial multidrug exporters
Ryosuke Nakashima Keisuke Sakurai Seiji Yamasaki Katsuhiko Hayashi Chikahiro Nagata Kazuki Hoshino Yoshikuni Onodera Kunihiko Nishino Akihito Yamaguchi
The multidrug efflux transporter AcrB and its homologues are important in the multidrug resistance of Gram-negative pathogens1, 2. However, despite efforts to develop efflux inhibitors3, clinically useful inhibitors are not available at present4, 5. Pyridopyrimidine derivatives are AcrB- and MexB-specific inhibitors that do not inhibit MexY6, 7; MexB and MexY are principal multidrug exporters in Pseudomonas aeruginosa8, 9, 10. We have previously determined the crystal structure of AcrB in the absence and presence of antibiotics11, 12, 13. Drugs were shown to be exported by a functionally rotating mechanism12 through tandem proximal and distal multisite drug-binding pockets13. Here we describe the first inhibitor-bound structures of AcrB and MexB, in which these proteins are bound by a pyridopyrimidine derivative. The pyridopyrimidine derivative binds tightly to a narrow pit composed of a phenylalanine cluster located in the distal pocket and sterically hinders the functional rotation. This pit is a hydrophobic trap that branches off from the substrate-translocation channel. Phe 178 is located at the edge of this trap in AcrB and MexB and contributes to the tight binding of the inhibitor molecule through a π–π interaction with the pyridopyrimidine ring. The voluminous side chain of Trp 177 located at the corresponding position in MexY prevents inhibitor binding. The structure of the hydrophobic trap described in this study will contribute to the development of universal inhibitors of MexB and MexY in P. aeruginosa.
