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Different Mutations in a P-type ATPase Transporter in Leishmania Parasites are Associated with Cross-resistance to

Christopher Fernandez-Prada1, Isabel M Vincent1, Marie-Christine Brotherton1

  • 1Centre de Recherche en Infectiologie du Centre de Recherche du CHU de Québec and Département de Microbiologie, Infectiologie et Immunologie, Faculté de Médecine, Université Laval, Québec, Québec, Canada.

Plos Neglected Tropical Diseases
|December 3, 2016
PubMed

Insights

Drug resistance in visceral leishmaniasis is a growing concern. This study reveals that mutations in the miltefosine transporter (MT) can lead to cross-resistance between amphotericin B (AmB) and miltefosine (MF), impacting treatment efficacy.

Area of Science:

  • Molecular parasitology
  • Drug resistance mechanisms
  • Leishmania biology

Background:

  • Visceral leishmaniasis, caused by Leishmania infantum, is a severe disease.
  • Liposomal amphotericin B (AmB) combined with miltefosine (MF) is a key treatment in India.
  • Miltefosine resistance is linked to mutations in the miltefosine transporter (MT).

Purpose of the Study:

  • To investigate if mutations in the miltefosine transporter (MT) are also found in Leishmania strains resistant to amphotericin B (AmB).
  • To understand the impact of AmB- or MF-induced MT mutations on drug uptake and lipid profiles.
  • To assess the risk of cross-resistance between AmB and MF treatments.

Main Methods:

  • Generation and analysis of Leishmania infantum mutants resistant to AmB or MF.
  • Sequencing of the miltefosine transporter (MT) gene in resistant mutants.
  • Assessment of drug translocation/uptake and lipidomic profiling (phospholipids, cyclopropanated fatty acids, inositolphosphoceramides).

Main Results:

  • Mutations in the miltefosine transporter (MT) were identified in both AmB- and MF-resistant Leishmania infantum.
  • MF-induced MT mutations, but not AmB-induced ones, significantly altered MF uptake.
  • Both AmB- and MF-selected MT mutations profoundly impacted lipid species, including phospholipids and inositolphosphoceramides, suggesting a link to cross-resistance.

Conclusions:

  • Mutations in the miltefosine transporter (MT) play a role in resistance to both amphotericin B (AmB) and miltefosine (MF).
  • AmB and MF treatments can induce MT mutations that alter lipid metabolism, potentially leading to cross-resistance.
  • Current sequential or co-treatment strategies using AmB and MF carry a risk of promoting cross-resistance in visceral leishmaniasis.

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