{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T06:01:01Z","timestamp":1785564061938,"version":"3.56.0"},"reference-count":68,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[2016,7,1]],"date-time":"2016-07-01T00:00:00Z","timestamp":1467331200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Protozoan parasites of the<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania donovani<\/jats:named-content>complex are the causative agents of visceral leishmaniasis (VL), the most severe form of leishmaniasis, with high rates of mortality if left untreated.<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Leishmania<\/jats:named-content>parasites are transmitted to humans through the bite of infected female sandflies (Diptera:<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">Phlebotominae<\/jats:named-content>), and approximately 500,000 new cases of VL are reported each year. In the absence of a safe human vaccine, chemotherapy, along with vector control, is the sole tool with which to fight the disease. Miltefosine (hexadecylphosphatidylcholine [HePC]), an antitumoral drug, is the only successful oral treatment for VL. In the current study, we describe the phenotypic traits of<jats:named-content xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" content-type=\"genus-species\" xlink:type=\"simple\">L. donovani<\/jats:named-content>clonal lines that have acquired resistance to HePC. We performed whole-genome and RNA sequencing of these resistant lines to provide an inclusive overview of the multifactorial acquisition of experimental HePC resistance, circumventing the challenge of identifying changes in membrane-bound proteins faced by proteomics. This analysis was complemented by assessment of the<jats:italic>in vitro<\/jats:italic>infectivity of HePC-resistant parasites. Our work underscores the importance of complementary \u201comics\u201d to acquire the most comprehensive insight for multifaceted processes, such as HePC resistance.<\/jats:p>","DOI":"10.1128\/aac.00478-16","type":"journal-article","created":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T04:08:19Z","timestamp":1461643699000},"page":"4089-4100","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":23,"title":["Genomic Appraisal of the Multifactorial Basis for<i>In Vitro<\/i>Acquisition of Miltefosine Resistance in Leishmania donovani"],"prefix":"10.1128","volume":"60","author":[{"given":"P.","family":"Vacchina","sequence":"first","affiliation":[{"name":"Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B.","family":"Norris-Mullins","sequence":"additional","affiliation":[{"name":"Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. A.","family":"Abeng\u00f3zar","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas (CIB), CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. G.","family":"Viamontes","sequence":"additional","affiliation":[{"name":"Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J.","family":"Sarro","sequence":"additional","affiliation":[{"name":"Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. T.","family":"Stephens","sequence":"additional","affiliation":[{"name":"Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. E.","family":"Pfrender","sequence":"additional","affiliation":[{"name":"Genomics and Bioinformatics Core Facility, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L.","family":"Rivas","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas (CIB), CSIC, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. A.","family":"Morales","sequence":"additional","affiliation":[{"name":"Eck Institute for Global Health, Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0703678104"},{"key":"e_1_3_3_3_2","unstructured":"World Health Organization. 2010. Control of the leishmaniases. World Health Organization Geneva Switzerland."},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01233-08"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/318122"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cis474"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.47.8.2397-2403.2003"},{"key":"e_1_3_3_8_2","first-page":"49965","article-title":"Functional cloning of the miltefosine transporter","volume":"278","author":"Perez-Victoria FJ","year":"2003","unstructured":"Perez-Victoria FJ, Gamarro F, Ouellette M, Castanys S. 2003. Functional cloning of the miltefosine transporter. A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J Biol Chem 278:49965\u201349971.","journal-title":"A novel P-type phospholipid translocase from Leishmania involved in drug resistance. J Biol Chem"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M605214200"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001657"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/cid\/cit102"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.9.2468-2474.2001"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2007.05653.x"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2007.12.007"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpara.2008.03.005"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.2014.916614"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1111\/1574-6976.12032"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-679X(08)61846-4"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02224-13"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00436-014-3835-7"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bmcl.2008.10.089"},{"key":"e_1_3_3_22_2","first-page":"Unit 15.18","article-title":"High-throughput real-time quantitative reverse transcription PCR","volume":"15","author":"Bookout AL","year":"2006","unstructured":"Bookout AL, Cummins CL, Mangelsdorf DJ, Pesola JM, Kramer MF. 2006. High-throughput real-time quantitative reverse transcription PCR. Curr Protoc Mol Biol Chapter 15:Unit 15.18.","journal-title":"Curr Protoc Mol Biol Chapter"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004244"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp851"},{"key":"e_1_3_3_25_2","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: a practical and powerful approach to multiple testing","volume":"57","author":"Benjamini Y","year":"1995","unstructured":"Benjamini Y, Hochberg Y. 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B 57:289\u2013300.","journal-title":"J R Stat Soc Ser B"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn176"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp324"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/0471250953.bi1110s43"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.107524.110"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1006\/expr.2001.4656"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00065-11"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2011.83"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0012443"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(03)00947-1"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00587-08"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.E02-08-0501"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1101\/gr.123430.111"},{"key":"e_1_3_3_38_2","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1042\/bj3560335","article-title":"Characterization of a differentially expressed protein that shows an unusual localization to intracellular membranes in Leishmania major","volume":"356","author":"Knuepfer E","year":"2001","unstructured":"Knuepfer E, Stierhof YD, McKean PG, Smith DF. 2001. Characterization of a differentially expressed protein that shows an unusual localization to intracellular membranes in Leishmania major. Biochem J 356:335\u2013344.","journal-title":"Biochem J"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-8579(03)00125-0"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.7.2677-2686.2005"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12374"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00030-11"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijpddr.2014.09.005"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001512"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msp214"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.1.406"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2958.2006.05060.x"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00216-014-7772-1"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj3100225"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2199-5-3"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914768107"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.11.3307"},{"key":"e_1_3_3_53_2","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1074\/mcp.M600319-MCP200","article-title":"A proteomics screen implicates HSP83 and a small kinetoplastid calpain-related protein in drug resistance in Leishmania donovani clinical field isolates by modulating drug-induced programmed cell death","volume":"6","author":"Vergnes B","year":"2007","unstructured":"Vergnes B, Gourbal B, Girard I, Sundar S, Drummelsmith J, Ouellette M. 2007. A proteomics screen implicates HSP83 and a small kinetoplastid calpain-related protein in drug resistance in Leishmania donovani clinical field isolates by modulating drug-induced programmed cell death. Mol Cell Proteomics 6:88\u2013101.","journal-title":"Mol Cell Proteomics"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2010.01439.x"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0020-7519(01)00346-0"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.9.2342"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20121262"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04231-14"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.55.11.2802-2806.1987"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.6701528"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1017\/S0031182011001120"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0003948"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0001664"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molbiopara.2007.07.007"},{"key":"e_1_3_3_65_2","doi-asserted-by":"publisher","DOI":"10.1021\/ac303064a"},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2014.05.010"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijantimicag.2008.01.032"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0065467"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pntd.0002527"}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00478-16","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.00478-16","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T23:38:19Z","timestamp":1718494699000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.00478-16"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7]]},"references-count":68,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2016,7]]}},"alternative-id":["10.1128\/AAC.00478-16"],"URL":"https:\/\/doi.org\/10.1128\/aac.00478-16","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,7]]},"assertion":[{"value":"2016-03-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-04-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2016-06-20","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}