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The inability of existing therapies to treat multidrug\u2010resistant pathogens has been recognized as an important challenge of the 21st century. Efflux pumps are important in both intrinsic and acquired bacterial resistance and identification of small molecule efflux pump inhibitors (EPIs), capable of restoring the effectiveness of available antibiotics, is an active research field. In the last two decades, much effort has been made to identify novel EPIs. However, none of them has so far been approved for therapeutic use.<\/jats:p>\n                  <jats:p>\n                    In this article, we explore different structural families of currently known EPIs for multidrug resistance efflux systems in the most extensively studied pathogens (NorA in\n                    <jats:italic>Staphylococcus aureus<\/jats:italic>\n                    , AcrAB\u2010TolC in\n                    <jats:italic>Escherichia coli<\/jats:italic>\n                    , and MexAB\u2010OprM in\n                    <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                    ). Both synthetic and natural compounds are described, with structure\u2010activity relationship studies and optimization processes presented systematically for each family individually. In vitro activities against selected test strains are presented in a unifying manner for all the EPIs described, together with the most important toxicity, pharmacokinetic and in vivo efficacy data. A critical evaluation of lead\u2010likeness characteristics and the potential for clinical development of the most promising inhibitors of the three efflux systems is described. This overview of EPIs is a good starting point for the identification of novel effective antibacterial drugs.\n                  <\/jats:p>","DOI":"10.1002\/med.21591","type":"journal-article","created":{"date-parts":[[2019,4,20]],"date-time":"2019-04-20T01:33:13Z","timestamp":1555723993000},"page":"2460-2504","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":193,"title":["Efflux pump inhibitors of clinically relevant multidrug resistant bacteria"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3147-4180","authenticated-orcid":false,"given":"Andra\u017e","family":"Lamut","sequence":"first","affiliation":[{"name":"Chair of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucija","family":"Peterlin Ma\u0161i\u010d","sequence":"additional","affiliation":[{"name":"Chair of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danijel","family":"Kikelj","sequence":"additional","affiliation":[{"name":"Chair of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tihomir","family":"Toma\u0161i\u010d","sequence":"additional","affiliation":[{"name":"Chair of Pharmaceutical Chemistry, Faculty of Pharmacy University of Ljubljana  Ljubljana Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,19]]},"reference":[{"key":"e_1_2_9_1_2_1","doi-asserted-by":"publisher","DOI":"10.2174\/0929867323666160304150522"},{"key":"e_1_2_9_1_3_1","unstructured":"World Health Organization. Antimicrobial resistance: global report on surveillance. 2014.http:\/\/apps.who.int\/iris\/bitstream\/handle\/10665\/112642\/9789241564748_eng.pdf;jsessionid=9CD00D9D8AFD2367340FCB5557B1426D?sequence=1. Accessed 15 November 2018."},{"key":"e_1_2_9_1_4_1","unstructured":"World Health Organization. WHO publishes list of bacteria for which new antibiotics are urgently needed. World Health Organization.http:\/\/www.who.int\/news\u2010room\/detail\/27\u201002\u20102017\u2010who\u2010publishes\u2010list\u2010of\u2010bacteria\u2010for\u2010which\u2010new\u2010antibiotics\u2010are\u2010urgently\u2010needed. 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