Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response

Alpizar-Sosa, E. A. et al. (2022) Amphotericin B resistance in Leishmania mexicana: Alterations to sterol metabolism and oxidative stress response. PLoS Neglected Tropical Diseases, 16(9), e0010779. (doi: 10.1371/journal.pntd.0010779) (PMID:36170238) (PMCID:PMC9581426)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Burchmore, Dr Richard and Donachie, Ms Anne Marie and Weidt, Dr Stefan and BINTI ITHNIN, NUR RAIHANA and Pountain, Andrew and Barrett, Professor Michael and Dickie, Dr Emily and Alpizar Sosa, Edubiel Arturo and Ritchie, Mr Ryan
Creator Roles:
Alpizar-Sosa, E. A.Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Writing – original draft, Writing – review and editing
Binti Ithnin, N. R.Formal analysis, Funding acquisition, Investigation, Methodology
Pountain, A. W.Formal analysis, Methodology, Writing – review and editing
Weidt, S. K.Formal analysis, Investigation, Methodology
Donachie, A. M.Investigation, Methodology
Ritchie, R.Investigation, Methodology
Dickie, E. A.Writing – review and editing
Burchmore, R. J.S.Supervision
Barrett, M. P.Conceptualization, Funding acquisition, Supervision, Writing – original draft, Writing – review and editing
Authors: Alpizar-Sosa, E. A., Binti Ithnin, N. R., Wei, W., Pountain, A. W., Weidt, S. K., Donachie, A. M., Ritchie, R., Dickie, E. A., Burchmore, R. J.S., Denny, P. W., and Barrett, M. P.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:PLoS Neglected Tropical Diseases
Publisher:Public Library of Science
ISSN (Online):1935-2735
Published Online:28 September 2022
Copyright Holders:This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose
First Published:First published in PLoS Neglected Tropical Diseases 16(9): e0010779
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
304784Bridging epigenetic, metabolism and cell cycle in pathogenic trypanosomatidsMichael BarrettMedical Research Council (MRC)MR/S019650/1III - Parasitology
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology