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Nature:研究人员另辟蹊径研发抗菌新药

日前,日本一个研究小组在《自然》杂志网络版上报告说,他们弄清了细菌细胞膜上的转运蛋白的立体结构,转运蛋白能将药物排出细胞从而让细菌产生抗药性。这一发现有望帮助研发抗菌新药。

东京大学的研究小组以耐受高温环境的嗜热古菌的转运蛋白为模型,使其在脂质中结晶,然后利用X射线详细分析了其立体结构。最终确认了其负责直接排出抗生物质的部分。研究人员将氨基酸连接成环状形成肽,成功阻止了嗜热古菌转运蛋白功能,使其无法排出抗生物质。

多重耐药菌是指有多重耐药性的病原菌,多种抗生物质对其都无法发挥作用。研究小组认为,如果能够研发出阻碍多重耐药菌转运蛋白功能的物质,就有望开发强有力的抗菌新药。

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Structural basis for the drug extrusion mechanism by a MATE multidrug transporter

Nature, 27 March 2013 | doi:10.1038/nature12014

Multidrug and toxic compound extrusion (MATE) family transporters are conserved in the three primary domains of life (Archaea, Bacteria and Eukarya), and export xenobiotics using an electrochemical gradient of H+ or Na+ across the membrane. MATE transporters confer multidrug resistance to bacterial pathogens and cancer cells7, thus causing critical reductions in the therapeutic efficacies of antibiotics and anti-cancer drugs, respectively. Therefore, the development of MATE inhibitors has long been awaited in the field of clinical medicine. Here we present the crystal structures of the H+-driven MATE transporter from Pyrococcus furiosus in two distinct apo-form conformations, and in complexes with a derivative of the antibacterial drug norfloxacin and three in vitro selected thioether-macrocyclic peptides, at 2.1–3.0 Å resolutions. The structures, combined with functional analyses, show that the protonation of Asp 41 on the amino (N)-terminal lobe induces the bending of TM1, which in turn collapses the N-lobe cavity, thereby extruding the substrate drug to the extracellular space. Moreover, the macrocyclic peptides bind the central cleft in distinct manners, which correlate with their inhibitory activities. The strongest inhibitory peptide that occupies the N-lobe cavity may pave the way towards the development of efficient inhibitors against MATE transporters.

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