skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Structural basis for the blockade of MATE multidrug efflux pumps

Authors:
; ; ;  [1]
  1. Rosalind
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
UNIVERSITY
OSTI Identifier:
1245872
Resource Type:
Journal Article
Resource Relation:
Journal Name: Nature Communications; Journal Volume: 6; Journal Issue: 7995
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Radchenko, Martha, Symersky, Jindrich, Nie, Rongxin, and Lu, Min. Structural basis for the blockade of MATE multidrug efflux pumps. United States: N. p., 2016. Web. doi:10.1038/ncomms8995.
Radchenko, Martha, Symersky, Jindrich, Nie, Rongxin, & Lu, Min. Structural basis for the blockade of MATE multidrug efflux pumps. United States. doi:10.1038/ncomms8995.
Radchenko, Martha, Symersky, Jindrich, Nie, Rongxin, and Lu, Min. 2016. "Structural basis for the blockade of MATE multidrug efflux pumps". United States. doi:10.1038/ncomms8995.
@article{osti_1245872,
title = {Structural basis for the blockade of MATE multidrug efflux pumps},
author = {Radchenko, Martha and Symersky, Jindrich and Nie, Rongxin and Lu, Min},
abstractNote = {},
doi = {10.1038/ncomms8995},
journal = {Nature Communications},
number = 7995,
volume = 6,
place = {United States},
year = 2016,
month = 6
}
  • Multidrug and toxic compound extrusion (MATE) transporters underpin multidrug resistance by using the H + or Na + electrochemical gradient to extrude different drugs across cell membranes. MATE transporters can be further parsed into the DinF, NorM and eukaryotic subfamilies based on their amino-acid sequence similarity. Here we report the 3.0 Å resolution X-ray structures of a protonation-mimetic mutant of an H +-coupled DinF transporter, as well as of an H +-coupled DinF and a Na +-coupled NorM transporters in complexes with verapamil, a small-molecule pharmaceutical that inhibits MATE-mediated multidrug extrusion. Combining structure-inspired mutational and functional studies, we confirm themore » biological relevance of our crystal structures, reveal the mechanistic differences among MATE transporters, and suggest how verapamil inhibits MATE-mediated multidrug efflux. Our findings offer insights into how MATE transporters extrude chemically and structurally dissimilar drugs and could inform the design of new strategies for tackling multidrug resistance.« less
  • No abstract prepared.
  • Antibiotic resistance is a major threat to human welfare. Inhibitors of multidrug efflux pumps (EPIs) are promising alternative therapeutics that could revive activities of antibiotics and reduce bacterial virulence. Identification of new druggable sites for inhibition is critical for developing effective EPIs, especially in light of constantly emerging resistance. We describe new EPIs that interact with and possibly inhibit the function of periplasmic membrane fusion proteins, critical components of efflux pumps that are responsible for the activation of the transporter and the recruitment of the outer-membrane channel. The discovered EPIs bind to AcrA, a component of the prototypical AcrAB-TolC pump,more » change its structure in vivo, inhibit efflux of fluorescent probes and potentiate the activities of antibiotics in Escherichia coli cells. These findings expand the chemical and mechanistic diversity of EPIs, suggest the mechanism for regulation of the efflux pump assembly and activity, and provide a promising path for reviving the activities of antibiotics in resistant bacteria.« less