A Multiplatform Metabolomic Approach to the Basis of Antimonial Action and Resistance in Leishmania infantum

David Rojo; Gisele A B Canuto; Emerson A Castilho-Martins; Marina F M Tavares; Coral Barbas; Ángeles López-Gonzálvez; Luis Rivas

doi:10.1371/journal.pone.0130675

A Multiplatform Metabolomic Approach to the Basis of Antimonial Action and Resistance in Leishmania infantum

PLoS One. 2015 Jul 10;10(7):e0130675. doi: 10.1371/journal.pone.0130675. eCollection 2015.

Authors

David Rojo¹, Gisele A B Canuto², Emerson A Castilho-Martins³, Marina F M Tavares⁴, Coral Barbas¹, Ángeles López-Gonzálvez¹, Luis Rivas⁵

Affiliations

¹ Centro de Metabolomica y Bioanalisis (CEMBIO), Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU, Facultad de Farmacia, Universidad CEU San Pablo, Campus Monteprincipe, Boadilla del Monte, 28668, Madrid, Spain.
² Centro de Metabolomica y Bioanalisis (CEMBIO), Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU, Facultad de Farmacia, Universidad CEU San Pablo, Campus Monteprincipe, Boadilla del Monte, 28668, Madrid, Spain; Institute of Chemistry, University of São Paulo (USP), Campus São Paulo, São Paulo, 05508-000, São Paulo, Brazil.
³ Centro de Metabolomica y Bioanalisis (CEMBIO), Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU, Facultad de Farmacia, Universidad CEU San Pablo, Campus Monteprincipe, Boadilla del Monte, 28668, Madrid, Spain; Colegiado de Medicina, Universidade Federal do Amapá, Macapá, AP, Brazil.
⁴ Institute of Chemistry, University of São Paulo (USP), Campus São Paulo, São Paulo, 05508-000, São Paulo, Brazil.
⁵ Centro de Investigaciones Biológicas (CSIC), Unidad Asociada Interacciones, Metabolismo y Bioanálisis CSIC-CEU, Ramiro de Maeztu 9, 28040, Madrid, Spain.

Abstract

There is a rising resistance against antimony drugs, the gold-standard for treatment until some years ago. That is a serious problem due to the paucity of drugs in current clinical use. In a research to reveal how these drugs affect the parasite during treatment and to unravel the underlying basis for their resistance, we have employed metabolomics to study treatment in Leishmania infantum promastigotes. This was accomplished first through the untargeted analysis of metabolic snapshots of treated and untreated parasites both resistant and responders, utilizing a multiplatform approach to give the widest as possible coverage of the metabolome, and additionally through novel monitoring of the origin of the detected alterations through a 13C traceability experiment. Our data stress a multi-target metabolic alteration with treatment, affecting in particular the cell redox system that is essential to cope with detoxification and biosynthetic processes. Additionally, relevant changes were noted in amino acid metabolism. Our results are in agreement with other authors studying other Leishmania species.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimony / pharmacology*
Antiprotozoal Agents / pharmacology*
Chromatography, Liquid / methods
Drug Resistance*
Humans
Leishmania infantum / drug effects*
Leishmania infantum / metabolism
Leishmaniasis, Visceral / drug therapy*
Leishmaniasis, Visceral / parasitology
Metabolome / drug effects*
Metabolomics / methods
Tandem Mass Spectrometry / methods

Substances

Antiprotozoal Agents
Antimony

Grants and funding

This work was supported by grants from Spanish Ministry of Economy and Competitiveness (CTQ2014-55279-R) (CB) and European Aeronautic Defence and Space Company – Construcciones Aeronáuticas SA and Brazilian Air Force (FAB) (GC and EC) and from FIS PS12-02706 and VI PN de I+D+I 2008-2011, Instituto de Salud Carlos III Subdirección General de Redes y Proyectos Cooperativos RD 12/0018/0007 (http://www.isciii.es/ISCIII/es/) and RD06/0021/0006-FEDER (LR). DR received a fellowship from the Spanish Ministry of Economy and Competitiveness (formerly MICINN). GABC is thankful to FAPESP for a graduate fellowship (http://www.fapesp.br/en/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.