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

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.