Publication
Title
Miltefosine enhances the fitness of a non-virulent drug-resistant Leishmania infantum strain
Author
Abstract
Objectives: Miltefosine is currently the only oral drug for visceral leishmaniasis, and although deficiency in an aminophospholipidimiltefosine transporter (MT) is sufficient to elicit drug resistance, very few naturally miltefosine-resistant (MIL-R) strains have yet been isolated. This study aimed to make a detailed analysis of the impact of acquired miltefosine resistance and miltefosine treatment on in vivo infection. Methods: Bioluminescent versions of a MIL-R strain and its syngeneic parental line were generated by ntegration of the red-shifted firefly luciferase PpyRE9. The fitness of both lines was compared in vitro (growth rate, metacyclogenesis and macrophage infectivity) and in BALB/c mice through non-invasive bioluminescence imaging under conditions with and without drug pressure. Results: This study demonstrated a severe fitness loss of MT-deficient paras tes, resulting in a complete inability to multiply and cause a typical visceral leishmaniasis infection pattern in BALB/c mice. The observed fitness loss could not be rescued by host immune suppression with cyclophosphamide, whereas episomal reconstitution with a wild-type MT restored parasite virulence, hence linking parasite fitness to MT mutation. Remarkably, in vivo miltefosine treatment or in vitro miltefosine pre-exposure significantly rescued MIL-R parasite virulence. The in vitro pre-exposed MIL-R promastigotes showed a longer and more slender morphology, suggesting an altered membrane composition. Conclusions: The profound fitness loss of MT-deficient parasites most likely explains the low frequency of MIL-R clinical isolates. The observation that miltefosine can reverse this phenotype indicates a drug dependency of the MT-deficient parasites and emphasizes the importance of resistance profiling prior to miltefosine administration.
Language
English
Source (journal)
The journal of antimicrobial chemotherapy. - London, 1975, currens
Publication
London : 2019
ISSN
0305-7453 [print]
1460-2091 [online]
DOI
10.1093/JAC/DKY450
Volume/pages
74 :2 (2019) , p. 395-406
ISI
000460473100017
Pubmed ID
30412253
Full text (Publisher's DOI)
Full text (publisher's version - intranet only)
UAntwerpen
Faculty/Department
Research group
Project info
Veterinary and human parasitology.
Dynamics and mechanisms of paromomycin and miltefosine drug-resistance in the protozoan parasite Leishmania.
Identifying factors involved in miltefosine or amphotericin B treatment failure in visceral leishmaniasis.
Study of miltefosine resistance mechanisms and dynamics through experimental selection of miltefosine-resistant Leishmania amastigo.
The role of parasite sanctuary sites and interaction with Kupffer cells in treatment failure of Visceral Leishmaniasis.
The role of parasite sanctuary sites and interaction with Kupffer cells in treatment failure of Visceral Leishmaniasis
Towards new concepts in anti-Leishmania treatment by modifying the interplay between sand fly transmitted parasites and the host innate immune system
Publication type
Subject
Affiliation
Publications with a UAntwerp address
External links
Web of Science
Record
Identifier
Creation 04.04.2019
Last edited 02.10.2024
To cite this reference