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A Parasite Rescue and Transformation Assay for Antileishmanial Screening Against Intracellular Leishmania donovani Amastigotes in THP1 Human Acute Monocytic Leukemia Cell Line
12:22

A Parasite Rescue and Transformation Assay for Antileishmanial Screening Against Intracellular Leishmania donovani Amastigotes in THP1 Human Acute Monocytic Leukemia Cell Line

Published on: December 30, 2012

Characterization of sinefungin-resistant Leishmania donovani promastigotes

M A Phelouzat1, F Lawrence, M Robert-Gero

  • 1Institut de Chimie des Substances Naturelles, CNRS, Gif sur Yvette, France.

Parasitology Research
|January 1, 1993
PubMed

Insights

Leishmania donovani developed resistance to sinefungin (SF) through distinct mechanisms. Resistant strains showed reduced SF levels, with one altering protein methylase affinity and the other modifying polyamine precursor biosynthesis.

Area of Science:

  • * Parasitology
  • * Molecular Biology
  • * Drug Resistance Mechanisms

Background:

  • * Sinefungin (SF) is a nucleoside antibiotic structurally related to S-adenosylmethionine (AdoMet).
  • * Leishmania donovani is a parasite responsible for visceral leishmaniasis.
  • * Understanding drug resistance in Leishmania is crucial for developing effective treatments.

Purpose of the Study:

  • * To generate and characterize sinefungin-resistant Leishmania donovani promastigote strains.
  • * To investigate the mechanisms underlying sinefungin resistance in these strains.
  • * To demonstrate that pleiotropic drug resistance can arise via diverse pathways.

Main Methods:

  • * Induction of drug resistance by gradually increasing sinefungin pressure.
  • * Culturing and selection of resistant promastigote clones.
  • * High-performance liquid chromatography (HPLC) for intracellular drug quantification.
  • * Analysis of protein methylase affinity and polyamine precursor biosynthesis.

Main Results:

  • * Generated stable sinefungin-resistant Leishmania donovani clones with 10,000-fold higher tolerance.
  • * Resistant clones exhibited significantly reduced intracellular sinefungin levels.
  • * One clone showed decreased affinity of protein methylases for SF.
  • * The other clone displayed modifications in polyamine precursor biosynthesis.

Conclusions:

  • * Leishmania donovani can develop specific and stable resistance to sinefungin.
  • * Resistance mechanisms are diverse, involving altered drug uptake, target affinity, or metabolic pathways.
  • * This highlights the adaptability of parasites in developing resistance to drugs with multiple targets.

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