Beyond antibiotic resistance: evidence for resistance-nodulation-division (RND) efflux pumps as virulence determinants

SUMMARYEarly in evolution, cells acquired the ability to use energy to export waste and toxic products against a concentration gradient. In Gram-negative bacteria, the resistance-nodulation-cell division (RND) superfamily of multi-subunit efflux pumps transport toxic molecules to the extracellular milieu. RND efflux pumps require cell-membrane proton motive force to export a wide range of substrates. Within the RND superfamily, Hydrophobe/Amphiphile Efflux 1 (HAE-1) family members have been studied extensively for their critical role in exporting structurally diverse antibiotics and, consequently, their contributions to multidrug resistance. However, HAE-1 RND efflux pumps are also required for pathogen survival in the mammalian host when antibiotics are absent. Here, we investigate the role of HAE-1 RND efflux pumps as virulence determinants. We analyze the genetic evidence that Gram-negative bacterial pathogens require HAE-1 RND efflux pumps to cause infection and briefly discuss the development of therapeutic and prophylactic approaches to interfere with HAE-1 RND efflux pump activity as a complement to existing antibiotics.