The hydrophobic trap-the Achilles heel of RND efflux pumps

Res Microbiol. 2018 Sep-Oct;169(7-8):393-400. doi: 10.1016/j.resmic.2017.11.001. Epub 2017 Nov 13.


Resistance-nodulation-division (RND) superfamily efflux pumps play a major role in multidrug resistance (MDR) of Gram-negative pathogens by extruding diverse classes of antibiotics from the cell. There has been considerable interest in developing efflux pump inhibitors (EPIs) of RND pumps as adjunctive therapies. The primary challenge in EPI discovery has been the highly hydrophobic, poly-specific substrate binding site of the target. Recent findings have identified the hydrophobic trap, a narrow phenylalanine-lined groove in the substrate-binding site, as the "Achilles heel" of the RND efflux pumps. In this review, we will examine the hydrophobic trap as an EPI target and two chemically distinct series of EPIs that bind there.

Keywords: Adjunctive therapy; Efflux pump; Efflux pump inhibitor; Hydrophobic trap; RND superfamily.

Publication types

  • Review

MeSH terms

  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacterial Proteins / antagonists & inhibitors
  • Bacterial Proteins / chemistry*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Binding Sites
  • Drug Design
  • Drug Resistance, Multiple, Bacterial
  • Gram-Negative Bacteria / chemistry
  • Gram-Negative Bacteria / drug effects
  • Gram-Negative Bacteria / genetics
  • Gram-Negative Bacteria / metabolism*
  • Hydrophobic and Hydrophilic Interactions
  • Membrane Transport Proteins / chemistry*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Multigene Family


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Membrane Transport Proteins