In-depth proteomics analysis of a Leishmania infantum strain selected in vitro for miltefosine resistance

ABSTRACT: Visceral Leishmaniasis (VL) is a neglected disease caused Leishmania parasites. Although significant morbidity and mortality in tropical and subtropical regions of the world are associated to VL, 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. Also, 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.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Leishmania Infantum

SUBMITTER: Jacek Wisniewski  

LAB HEAD: Jacek R Wisniewski

PROVIDER: PXD031912 | Pride | 2022-05-20

REPOSITORIES: Pride