Untargeted metabolomics to understand the basis of phenotypic differences in amphotericin B-resistant

Pountain, A. W. and Barrett, M. P. (2019) Untargeted metabolomics to understand the basis of phenotypic differences in amphotericin B-resistant. Wellcome Open Research, 4, 176. (doi: 10.12688/wellcomeopenres.15452.1) (PMID:32133420) (PMCID:PMC7041363)

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Abstract

Background: Protozoan Leishmania parasites are responsible for a range of clinical infections that represent a substantial challenge for global health. Amphotericin B (AmB) is increasingly used to treat Leishmania infection, so understanding the potential for resistance to this drug is an important priority. Previously we described four independently-derived AmB-resistant L. mexicana lines that exhibited resistance-associated genetic lesions resulting in altered sterol content. However, substantial phenotypic variation between these lines, including differences in virulence attributes, were not fully explained by these changes. Methods: To identify alterations in cellular metabolism potentially related to phenotypic differences between wild-type and AmB-resistant lines, we extracted metabolites and performed untargeted metabolomics by liquid chromatography-mass spectrometry. Results: We observed substantial differences in metabolite abundance between lines, arising in an apparently stochastic manner. Concerted remodeling of central carbon metabolism was not observed; however, in three lines, decreased abundance of several oligohexoses was observed. Given that the oligomannose mannogen is an important virulence factor in Leishmania, this could relate to loss of virulence in these lines. Increased abundance of the reduced forms of the oxidative stress-protective thiols trypanothione and glutathione was also observed in multiple lines. Conclusions: This dataset will provide a useful resource for understanding the molecular basis of drug resistance in Leishmania, and suggests a role for metabolic changes separate from the primary mechanism of drug resistance in determining the phenotypic profile of parasite lines subjected to experimental selection of resistance.

Item Type:Articles
Additional Information:Version 1; peer review: 2 approved.
Keywords:Leishmania, amphotericin B, drug resistance, metabolomics.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pountain, Andrew and Barrett, Professor Michael
Creator Roles:
Pountain, A. W.Conceptualization, Formal analysis, Investigation, Visualization, Writing – original draft
Barrett, M. P.Conceptualization, Funding acquisition, Supervision, Writing – original draft
Authors: Pountain, A. W., and Barrett, M. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Wellcome Open Research
Publisher:F1000Research
ISSN:2398-502X
ISSN (Online):2398-502X
Copyright Holders:Copyright © 2019 Pountain AW and Barrett MP
First Published:First published in Wellcome Open Research 4: 176
Publisher Policy:Reproduced under a Creative Commons License
Related URLs:
Data DOI:10.6084/m9.figshare.10059710.v1

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171661Molecular Functions in Disease PhD Studentship (2013-2017)Michael BarrettWellcome Trust (WELLCOTR)102462/Z/13/ZIII - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology