How resistance-nodulation-division (RND) efflux pumps contribute to virulence

In Gram-negative bacteria, multi-subunit efflux pumps transport molecules across the inner membrane, periplasm, and outer membrane to the extracellular environment. These efflux pumps include the Resistance-Nodulation-Cell Division (RND) superfamily, which utilize the membrane proton motive force to export a wide range of substrates against a concentration gradient. RND efflux pumps have been extensively studied for their fundamental role in the export of antibiotics, but they also play multifaceted roles in bacterial physiology. Notably, they are required for pathogen survival in the mammalian host when antibiotics are absent, an emerging aspect of their biology that is not well understood. Here, we analyze the evidence supporting several intertwined mechanistic hypotheses regarding the requirement for RND efflux pumps during infection. To do this, we explore why host- and bacterial-derived substrates need to be exported during pathogenesis, and the effects of proton translocation from the periplasm to the cytosol. We close by highlighting knowledge gaps and directions for future work regarding the role of RND efflux pumps in bacterial virulence.