Dr Edubiel Alpizar Sosa edubiel.a.alpizar-sosa@durham.ac.uk
Post Doctoral Research Associate
Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response
Alpizer-Sosa, E.A.; Ithnin, N.R.B.; Wei, W.; Pountain, A.W.; Weidt, A.K.; Donachie, A.M.; Ritchie, R.; Dickie, E.A; Burchmore, R.J.S.; Denny, P.W.; Barrett, M.P.
Authors
N.R.B. Ithnin
Dr Wenbin Wei wenbin.wei2@durham.ac.uk
Chief Experimental Officer (Bioinformatics)
A.W. Pountain
A.K. Weidt
A.M. Donachie
R. Ritchie
E.A Dickie
R.J.S. Burchmore
Professor Paul Denny p.w.denny@durham.ac.uk
Professor
M.P. Barrett
Abstract
Amphotericin B is increasingly used in treatment of leishmaniasis. Here, fourteen independent lines of Leishmania mexicana and one L. infantum line were selected for resistance to either amphotericin B or the related polyene antimicrobial, nystatin. Sterol profiling revealed that, in each resistant line, the predominant wild-type sterol, ergosta-5,7,24-trienol, was replaced by other sterol intermediates. Broadly, two different profiles emerged among the resistant lines. Whole genome sequencing then showed that these distinct profiles were due either to mutations in the sterol methyl transferase (C24SMT) gene locus or the sterol C5 desaturase (C5DS) gene. In three lines an additional deletion of the miltefosine transporter gene was found. Differences in sensitivity to amphotericin B were apparent, depending on whether cells were grown in HOMEM, supplemented with foetal bovine serum, or a serum free defined medium (DM). Metabolomic analysis after exposure to AmB showed that a large increase in glucose flux via the pentose phosphate pathway preceded cell death in cells sustained in HOMEM but not DM, indicating the oxidative stress was more significantly induced under HOMEM conditions. Several of the lines were tested for their ability to infect macrophages and replicate as amastigote forms, alongside their ability to establish infections in mice. While several AmB resistant lines showed reduced virulence, at least two lines displayed heightened virulence in mice whilst retaining their resistance phenotype, emphasising the risks of resistance emerging to this critical drug.
Citation
Alpizer-Sosa, E., Ithnin, N., Wei, W., Pountain, A., Weidt, A., Donachie, A., …Barrett, M. (2022). Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response. PLoS Neglected Tropical Diseases, 16(9), Article e0010779. https://doi.org/10.1371/journal.pntd.0010779
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 31, 2022 |
Online Publication Date | Sep 28, 2022 |
Publication Date | 2022 |
Deposit Date | Sep 7, 2022 |
Publicly Available Date | Oct 21, 2022 |
Journal | PLOS Neglected Tropical Diseases |
Print ISSN | 1935-2727 |
Electronic ISSN | 1935-2735 |
Publisher | Public Library of Science |
Peer Reviewed | Peer Reviewed |
Volume | 16 |
Issue | 9 |
Article Number | e0010779 |
DOI | https://doi.org/10.1371/journal.pntd.0010779 |
Public URL | https://durham-repository.worktribe.com/output/1194925 |
Files
Published Journal Article
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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/
Copyright Statement
This is an open access article, free of all<br />
copyright, and may be freely reproduced,<br />
distributed, transmitted, modified, built upon, or<br />
otherwise used by anyone for any lawful purpose.<br />
The work is made available under the Creative<br />
Commons CC0 public domain dedication.
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