In:
PLOS Neglected Tropical Diseases, Public Library of Science (PLoS), Vol. 16, No. 9 ( 2022-9-28), p. e0010779-
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.
Type of Medium:
Online Resource
ISSN:
1935-2735
DOI:
10.1371/journal.pntd.0010779
DOI:
10.1371/journal.pntd.0010779.g001
DOI:
10.1371/journal.pntd.0010779.g002
DOI:
10.1371/journal.pntd.0010779.g003
DOI:
10.1371/journal.pntd.0010779.g004
DOI:
10.1371/journal.pntd.0010779.g005
DOI:
10.1371/journal.pntd.0010779.g006
DOI:
10.1371/journal.pntd.0010779.t001
DOI:
10.1371/journal.pntd.0010779.s001
DOI:
10.1371/journal.pntd.0010779.s002
DOI:
10.1371/journal.pntd.0010779.s003
DOI:
10.1371/journal.pntd.0010779.s004
DOI:
10.1371/journal.pntd.0010779.s005
DOI:
10.1371/journal.pntd.0010779.s006
DOI:
10.1371/journal.pntd.0010779.s007
DOI:
10.1371/journal.pntd.0010779.s008
DOI:
10.1371/journal.pntd.0010779.s009
DOI:
10.1371/journal.pntd.0010779.s010
DOI:
10.1371/journal.pntd.0010779.s011
DOI:
10.1371/journal.pntd.0010779.s012
DOI:
10.1371/journal.pntd.0010779.s013
DOI:
10.1371/journal.pntd.0010779.s014
DOI:
10.1371/journal.pntd.0010779.s015
DOI:
10.1371/journal.pntd.0010779.s016
DOI:
10.1371/journal.pntd.0010779.s017
DOI:
10.1371/journal.pntd.0010779.s018
DOI:
10.1371/journal.pntd.0010779.s019
DOI:
10.1371/journal.pntd.0010779.s020
DOI:
10.1371/journal.pntd.0010779.s021
DOI:
10.1371/journal.pntd.0010779.s022
DOI:
10.1371/journal.pntd.0010779.s023
DOI:
10.1371/journal.pntd.0010779.r001
DOI:
10.1371/journal.pntd.0010779.r002
DOI:
10.1371/journal.pntd.0010779.r003
DOI:
10.1371/journal.pntd.0010779.r004
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2022
detail.hit.zdb_id:
2429704-5
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