革兰氏阴性菌AcrAB-TolC多药外排泵结构数据对抑制剂研发的启示

Structural insights into the AcrAB-TolC efflux pump of Gram-negative bacteria promote the development of pump inhibitors

摘要:

革兰氏阴性菌的多重耐药性已成为全球广泛聚焦的问题。近年研究发现，耐药结节细胞分化(resistance-nodulation-cell division，RND)家族外排泵的过表达，与革兰氏阴性菌的多重耐药性密切相关。在RND家族中，广泛存在于革兰氏阴性菌中的AcrAB-TolC外排泵被认为是导致多重耐药性的主要原因之一。为了开发有效的抑制剂，需要对AcrAB-TolC外排泵的结构有一个清晰的认识。以往对该外排泵结构的研究主要局限于体外采用X射线晶体学技术或冷冻电镜单颗粒分析技术来解析其单个组分或全泵的结构。细胞冷冻电子断层扫描技术为揭示AcrAB-TolC外排泵在天然细胞膜环境中的组装和运行机制提供了新的见解，本文综述了AcrAB-TolC不同层级的结构数据在研发外排泵抑制剂方面的贡献。

Abstract:

The emerging of multidrug resistance (MDR) in Gram-negative bacteria has aroused worldwide concern. Overexpression of efflux pumps, especially the resistance-nodulation-cell division (RND) efflux pumps, has been demonstrated to be closely associated with MDR in Gram-negative pathogens. In RND family, AcrAB-TolC efflux pump, which is widely present in Gram-negative bacteria, is a decisive factor of bacteria to develop MDR. To develop effective efflux pump inhibitors, we need to clear understand the structure of AcrAB-TolC. The available studies about the structure of this pump are limited to individual components or the whole pump structures determined by X-ray crystallography or single-particle cryo-electron microscopy. The recently developed cryo-electron tomography sheds new light on the assembly and operating mechanism of this pump in the native cell membrane environment. Here, we summarize the contributions of the structural data of AcrAB-TolC efflux pump to the discovery of pump inhibitors against antibiotic resistance in bacteria.