Pharmacometabolomics of meglumine antimoniate in patients with cutaneous leishmaniasis

Vargas, D. A., Prieto, M. D., Martínez-Valencia, A. J., Cossio, A., Burgess, K. E.V., Burchmore, R. J.S. and Gómez, M. A. (2019) Pharmacometabolomics of meglumine antimoniate in patients with cutaneous leishmaniasis. Frontiers in Pharmacology, 10, 657. (doi: 10.3389/fphar.2019.00657) (PMID:31281253) (PMCID:PMC6595045)

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Abstract

Control of cutaneous leishmaniasis (CL) in the Americas is dependent on chemotherapy with parenteral pentavalent antimonials. High rates of treatment failure urge the search for predictive and prognostic markers of therapeutic responsiveness. In this study, we aimed to identify biomarkers of therapeutic response during treatment with meglumine antimoniate (MA). We conducted untargeted metabolomic profiling of plasma samples from CL patients (n = 39; 25 who cured and 14 who did not cure), obtained before and at the end of treatment. Exposure to MA induced metabolic perturbations primarily reflecting alteration in long-chain fatty acid β-oxidation and energy production. Allantoin, N-acetylglutamine, taurine, and pyruvate were significantly more abundant in samples from patients who responded to treatment, and were predictive and prognostic of treatment outcome in this patient cohort (AUC > 0.7). In an ex vivo model of infection, allantoin but not taurine enhanced the MA-dependent killing of intracellular Leishmania (Viannia) panamensis. Our results support the participation of metabolites mediating antioxidant and wound healing responses in clinical cure of CL, revealing relationships between metabolism and immune responses in the outcome of antileishmanial treatment.

Item Type:Articles
Additional Information:This work was supported by US National Institutes of Health (NIH) grant R01AI104823 (https://www.niaid.nih.gov/) to MG, COLCIENCIAS grant 2229-65843177 contract no. 007-2015 to MG, and Newton-Caldas Fund grant 172715657 to RB and MG. DV and MP were supported, respectively, by COLCIENCIAS DSc student award 647 and Young Investigators and Innovators Program Contract Number 0552-2015.
Keywords:Pharmacology, cutaneous leishmaniasis, meglumine antimoniate, pharmacometabolomics, biomarkers, allantoin, taurine.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Burchmore, Dr Richard and Burgess, Dr Karl
Authors: Vargas, D. A., Prieto, M. D., Martínez-Valencia, A. J., Cossio, A., Burgess, K. E.V., Burchmore, R. J.S., and Gómez, M. A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Frontiers in Pharmacology
Publisher:Frontiers Media
ISSN:1663-9812
ISSN (Online):1663-9812
Copyright Holders:Copyright © 2019 Vargas, Prieto, Martínez-Valencia, Cossio, Burgess, Burchmore and Gómez
First Published:First published in Frontiers in Pharmacology 10: 657
Publisher Policy:Reproduced under a Creative Commons License

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