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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.<\/jats:p>","DOI":"10.1128\/mmbr.00278-24","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T14:00:19Z","timestamp":1763647219000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":7,"title":["Beyond antibiotic resistance: evidence for resistance-nodulation-division (RND) efflux pumps as virulence determinants"],"prefix":"10.1128","volume":"89","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7783-0876","authenticated-orcid":false,"given":"Corrella S.","family":"Detweiler","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02ttsq026","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular, Cellular, and Developmental Biology, University of Colorado at Boulder","place":["Boulder, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7212-3371","authenticated-orcid":true,"given":"Ilyas","family":"Alav","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03angcq70","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Microbes, Infection, and Microbiomes, School of Infection, Inflammation and Immunology, College of Medicine and Health, University of Birmingham","place":["Birmingham, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_1_2_2","first-page":"107","article-title":"The RND permease superfamily: an ancient, ubiquitous and diverse family that includes human disease and development proteins","volume":"1","author":"Tseng TT","year":"1999","unstructured":"Tseng TT, Gratwick KS, Kollman J, Park D, Nies DH, Goffeau A, Saier MH. 1999. 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