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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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| 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: | 1935-2727 |
| 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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