Do RND efflux pumps require protomeric cooperativity within the trimer to mediate antimicrobial resistance?

SUMMARY Gram-negative bacteria frequently use efflux pumps of the resistance-nodulation-cell division (RND) superfamily to extrude various toxic compounds out of the cell. In particular, the hydrophobe-amphiphile efflux 1 (HAE1) and heavy-metal efflux (HME)-RND families are critical for the export of antimicrobials and heavy metals, respectively. These efflux pumps assemble as trimers at the inner membrane of the bacterium. In this review, structural and functional data are summarized for several of these HAE1 and HME-RND efflux pumps from work performed in our laboratory and others. Experimental results and analyses suggest that individual protomers of these efflux pumps within their respective trimer function independently and in an uncoordinated manner to export substrates. Based on these observations, a molecular mechanism that governs substrate recognition and extrusion for these membrane proteins is proposed. It is our hope that researchers in the field will continue to build upon these efforts and employ various biophysical and biochemical methodologies to fully understand the mechanistic basis of important RND efflux systems.