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In addition to the intrinsic resistance to polymyxin E (colistin) conferred by\n                    <jats:italic>Neisseria eptA<\/jats:italic>\n                    , the plasmid-borne mobilized colistin resistance gene\n                    <jats:italic>mcr-1<\/jats:italic>\n                    has been disseminated globally since the first discovery in Southern China, in late 2015. However, the molecular mechanisms for both intrinsic and transferable resistance to colistin remain largely unknown. Here, we aim to address this gap in the knowledge of these proteins. Structural and functional analyses of EptA and MCR-1 and -2 have defined a conserved 12-residue cavity that is required for the entry of the lipid substrate, phosphatidylethanolamine (PE). The\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    data together have allowed us to visualize the similarities in catalytic activity shared by EptA and MCR-1 and -2. The expression of either EptA or MCR-1 or -2 is shown to remodel the surface of enteric bacteria (e.g.,\n                    <jats:named-content content-type=\"genus-species\">Escherichia coli<\/jats:named-content>\n                    ,\n                    <jats:named-content content-type=\"genus-species\">Salmonella enterica<\/jats:named-content>\n                    ,\n                    <jats:named-content content-type=\"genus-species\">Klebsiella pneumoniae<\/jats:named-content>\n                    , etc.), rendering them resistant to colistin. The parallels in the PE substrate-binding cavities among EptA, MCR-1, and MCR-2 provide a comprehensive understanding of both intrinsic and transferable colistin resistance. Domain swapping between EptA and MCR-1 and -2 reveals that the two domains (transmembrane [TM] region and\n                    <jats:underline>p<\/jats:underline>\n                    hospho\n                    <jats:underline>e<\/jats:underline>\n                    thanol\n                    <jats:underline>a<\/jats:underline>\n                    mine [PEA] transferase) are not functionally exchangeable. Taken together, the results represent a common mechanism for intrinsic and transferable PEA resistance to polymyxin, a last-resort antibiotic against multidrug-resistant pathogens.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:bold>IMPORTANCE<\/jats:bold>\n                    EptA and MCR-1 and -2 remodel the outer membrane, rendering bacteria resistant to colistin, a final resort against carbapenem-resistant pathogens. Structural and functional analyses of EptA and MCR-1 and -2 reveal parallel PE lipid substrate-recognizing cavities, which explains intrinsic and transferable colistin resistance in gut bacteria. A similar mechanism is proposed for the catalytic activities of EptA and MCR-1 and -2. Together, they constitute a common mechanism for intrinsic and transferable polymyxin resistance.\n                  <\/jats:p>","DOI":"10.1128\/mbio.02317-17","type":"journal-article","created":{"date-parts":[[2018,4,9]],"date-time":"2018-04-09T07:10:11Z","timestamp":1523257811000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":88,"title":["An Evolutionarily Conserved Mechanism for Intrinsic and Transferable Polymyxin Resistance"],"prefix":"10.1128","volume":"9","author":[{"given":"Yongchang","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Lei","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxia","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swaminath","family":"Srinivas","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youjun","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China"},{"name":"College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2018.02.006"},{"key":"e_1_3_2_3_2","volume-title":"Antimicrobial resistance: global report on surveillance, 2014","author":"World Health Organization","year":"2014","unstructured":"World Health Organization. 2014. Antimicrobial resistance: global report on surveillance, 2014. WHO, Geneva, Switzerland. http:\/\/apps.who.int\/iris\/bitstream\/10665\/112642\/1\/9789241564748_eng.pdf?ua=1."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(16)31079-0"},{"key":"e_1_3_2_5_2","volume-title":"Antibiotic resistance threats in the United States, 2013","author":"CDC","year":"2013","unstructured":"CDC. 2013. Antibiotic resistance threats in the United States, 2013. 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