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Although significant morbidity and mortality in tropical and subtropical regions of the world are associated with VL, the low investment for developing new treatment measures is chronic. Moreover, resistance and treatment failure are increasing for the main medications, but the emergence of resistance phenotypes is poorly understood at the protein level. Here, we analyzed the development of resistance to miltefosine upon experimental selection in a L. infantum strain. Time to miltefosine resistance emergence was ~six months and label-free quantitative mass-spectrometry-based proteomics analyses revealed that this process involves a remodeling of components of the membrane and mitochondrion, with significant increase in oxidative phosphorylation complexes, particularly on complex IV and ATP synthase, accompanied by increased energy metabolism mainly dependent on \u03b2-oxidation of fatty acids. Proteins canonically involved in ROS detoxification did not contribute to the resistant process whereas sterol biosynthesis enzymes could have a role in this development. Furthermore, changes in the abundance of proteins known to be involved in miltefosine resistance such as ABC transporters and phospholipid transport ATPase were detected. Together, our data show a more complete picture of the elements that make up the miltefosine resistance phenotype in L. infantum.<\/jats:p>","DOI":"10.3390\/proteomes10020010","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T21:34:29Z","timestamp":1648762469000},"page":"10","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum"],"prefix":"10.3390","volume":"10","author":[{"given":"Leonardo","family":"Saboia-Vahia","sequence":"first","affiliation":[{"name":"Grupo de Gen\u00f4mica Funcional de Parasitos (GFP), Instituto Ren\u00e9 Rachou, Fiocruz Minas, Belo Horizonte 30190-002, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6245-4185","authenticated-orcid":false,"given":"Patricia","family":"Cuervo","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek R.","family":"Wi\u015bniewski","sequence":"additional","affiliation":[{"name":"Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Planegg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4448-1398","authenticated-orcid":false,"given":"Geovane","family":"Dias-Lopes","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Biologia Molecular e Doen\u00e7as End\u00eamicas, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8900-6748","authenticated-orcid":false,"given":"Nathalia","family":"Pinho","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"},{"name":"Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Padr\u00f3n","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2939-7780","authenticated-orcid":false,"given":"Fernando","family":"de Pilla Varotti","sequence":"additional","affiliation":[{"name":"Research Center on Biological Chemistry (NQBio), Federal University of S\u00e3o Jo\u00e3o Del Rei, Divin\u00f3polis 35501-296, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvane Maria Fonseca","family":"Murta","sequence":"additional","affiliation":[{"name":"Grupo de Gen\u00f4mica Funcional de Parasitos (GFP), Instituto Ren\u00e9 Rachou, Fiocruz Minas, Belo Horizonte 30190-002, MG, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Alvar, J., V\u00e9lez, I.D., Bern, C., Herrero, M., Desjeux, P., Cano, J., Jannin, J., and de Boer, M. 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