Objectives: Increasing numbers of miltefosine treatment failures in visceral leishmaniasis therapy and reports of miltefosine resistance in the Indian subcontinent resulted in the recommendation to use liposomal amphotericin B as first-line therapy. Cross-resistance between miltefosine and amphotericin B has recently been documented, suggesting a role of mutations in the miltefosine transporter, a complex encoded by the MT and ROS3 genes. This study aimed to further explore the putative role of MT/ROS3 defects in the molecular basis of amphotericin B cross-resistance. Methods: The susceptibility profiles of different miltefosine-resistant Leishmania infantum strains with well-characterized mutations in the transporter complex and the corresponding episomally restored susceptible parasite lines were determined using both the routine extracellular promastigote assay and the intracellular amastigote assay. Results: In vitro amastigote and promastigote susceptibility testing of the two miltefosine-resistant and the episomally reconstituted L. infantum lines revealed full susceptibility to amphotericin B, despite the variable miltefosine susceptibility profile. Conclusions: Mutations present in either the MT and/or ROS3 gene are not sufficient to elicit higher tolerance to amphotericin B. Additional synergistic adaptations may be responsible for the miltefosine/amphotericin B cross-resistance described earlier.
Objectives: Increasing numbers of miltefosine treatment failures in visceral leishmaniasis therapy and reports of miltefosine resistance in the Indian subcontinent resulted in the recommendation to use liposomal amphotericin B as first-line therapy. Cross-resistance between miltefosine and amphotericin B has recently been documented, suggesting a role of mutations in the miltefosine transporter, a complex encoded by the MT and ROS3 genes. This study aimed to further explore the putative role of MT/ROS3 defects in the molecular basis of amphotericin B cross-resistance. Methods: The susceptibility profiles of different miltefosine-resistant Leishmania infantum strains with well-characterized mutations in the transporter complex and the corresponding episomally restored susceptible parasite lines were determined using both the routine extracellular promastigote assay and the intracellular amastigote assay. Results: In vitro amastigote and promastigote susceptibility testing of the two miltefosine-resistant and the episomally reconstituted L. infantum lines revealed full susceptibility to amphotericin B, despite the variable miltefosine susceptibility profile. Conclusions: Mutations present in either the MT and/or ROS3 gene are not sufficient to elicit higher tolerance to amphotericin B. Additional synergistic adaptations may be responsible for the miltefosine/amphotericin B cross-resistance described earlier.
Authors: Lieselotte Van Bockstal; Dimitri Bulté; Sarah Hendrickx; Jovana Sadlova; Petr Volf; Louis Maes; Guy Caljon Journal: Int J Parasitol Drugs Drug Resist Date: 2020-05-01 Impact factor: 4.077
Authors: Caroline R Espada; Rubens M Magalhães; Mario C Cruz; Paulo R Machado; Albert Schriefer; Edgar M Carvalho; Valentín Hornillos; João M Alves; Angela K Cruz; Adriano C Coelho; Silvia R B Uliana Journal: Int J Parasitol Drugs Drug Resist Date: 2019-02-25 Impact factor: 4.077
Authors: Daniela P Lage; Patrícia A F Ribeiro; Daniel S Dias; Débora V C Mendonça; Fernanda F Ramos; Lívia M Carvalho; Bethina T Steiner; Grasiele S V Tavares; Vívian T Martins; Amanda S Machado; João A Oliveira-da-Silva; Thaís T O Santos; Camila S Freitas; Jamil S Oliveira; Bruno M Roatt; Ricardo A Machado-de-Ávila; Maria V Humbert; Myron Christodoulides; Eduardo A F Coelho Journal: Vaccines (Basel) Date: 2020-06-09