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© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Visceral leishmaniasis (VL) is a neglected disease caused by Leishmania parasites. 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 β-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.

Details

Title
In-Depth Quantitative Proteomics Characterization of In Vitro Selected Miltefosine Resistance in Leishmania infantum
Author
Saboia-Vahia, Leonardo 1 ; Cuervo, Patricia 2   VIAFID ORCID Logo  ; Wiśniewski, Jacek R 3 ; Dias-Lopes, Geovane 4   VIAFID ORCID Logo  ; Pinho, Nathalia 2   VIAFID ORCID Logo  ; Padrón, Gabriel 5 ; Fernando de Pilla Varotti 6   VIAFID ORCID Logo  ; Silvane Maria Fonseca Murta 1 

 Grupo de Genômica Funcional de Parasitos (GFP), Instituto René Rachou, Fiocruz Minas, Belo Horizonte 30190-002, MG, Brazil 
 Laboratório de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil; [email protected] (P.C.); [email protected] (N.P.); [email protected] (G.P.); Rio de Janeiro Research Network on Neuroinflammation, Oswaldo Cruz Institute, Oswaldo Cruz Foundation, Rio de Janeiro 21040-360, RJ, Brazil 
 Biochemical Proteomics Group, Department of Proteomics and Signal Transduction, Max-Planck-Institute of Biochemistry, 82152 Planegg, Germany; [email protected] 
 Laboratório de Biologia Molecular e Doenças Endêmicas, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil; [email protected] 
 Laboratório de Pesquisa em Leishmanioses, Instituto Oswaldo Cruz, Fiocruz, Rio de Janeiro 21040-360, RJ, Brazil; [email protected] (P.C.); [email protected] (N.P.); [email protected] (G.P.) 
 Research Center on Biological Chemistry (NQBio), Federal University of São João Del Rei, Divinópolis 35501-296, MG, Brazil; [email protected] 
First page
10
Publication year
2022
Publication date
2022
Publisher
MDPI AG
e-ISSN
22277382
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2679808512
Copyright
© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.