Structural and Functional Diversity of Resistance-Nodulation-Cell Division Transporters.
Structural and Functional Diversity of Resistance-Nodulation-Cell Division Transporters.
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DOI：
10.1021/acs.chemrev.0c00621
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发表时间：
2021-05-12
期刊：
影响因子：
62.1
通讯作者：
Yu EW
中科院分区：
文献类型：
--
作者：
Klenotic PA;Moseng MA;Morgan CE;Yu EW
多药耐药（MDR）细菌是一个全球性的威胁，许多常见的感染变得越来越难以消除。虽然已经投入了大量的努力来开发有效的杀生物剂，但由于适应性耐药机制，许多一线抗生素的有效性已经降低。细菌膜蛋白属于耐药-增殖-细胞分裂（RND）超家族，在介导细菌对抗生素的耐药性中发挥重要作用。它们参与多药外排和细胞壁生物发生，将细菌病原体转化为即使对最后的抗生素也有抗性的“超级细菌”。本文综述了RND超家族的外排转运蛋白，重点介绍了内膜泵的组装和功能。这些泵对于从细胞中挤出抗生素以及将脂质部分转运到外膜以建立膜刚性和稳定性至关重要。我们分析了最近解决的细菌内膜外排泵的结构，以了解它们如何结合和运输底物。我们的累积数据表明，这些RND膜蛋白能够利用不同的寡聚化状态来实现特定的活性，包括形成MDR泵和细胞壁重塑机制，以确保细菌的存活。这种机制的洞察力，结合模拟对接技术，允许设计和优化新的外排泵抑制剂，以更有效地治疗感染，今天是困难的或不可能治愈。
Multidrug resistant (MDR) bacteria is a global threat with many common infections becoming increasingly difficult to eliminate. While significant effort has gone into the development of potent biocides, the effectiveness of many first-line antibiotics has been diminished due to adaptive resistance mechanisms. Bacterial membrane proteins belonging to the resistance-nodulation-cell division (RND) superfamily play significant roles in mediating bacterial resistance to antimicrobials. They participate in multidrug efflux and cell wall biogenesis to transform bacterial pathogens into “superbugs” that are resistant even to last resort antibiotics. In this review, we summarize the RND superfamily of efflux transporters, with a primary focus on the assembly and function of the inner membrane pumps. These pumps are critical for extrusion of antibiotics from the cell as well as the transport of lipid moieties to the outer membrane to establish membrane rigidity and stability. We analyze recently solved structures of bacterial inner membrane efflux pumps as to how they bind and transport their substrates. Our cumulative data indicate that these RND membrane proteins area able to utilize different oligomerization states to achieve particular activities, including forming MDR pumps and cell wall remodeling machineries, to ensure bacterial survival. This mechanistic insight, combined with simulated docking techniques, allows for the design and optimization of new efflux pump inhibitors to more effectively treat infections that today are difficult or impossible to cure.
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影响因子：
3.7
作者：
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