title: Different Mutations in a P-type ATPase Transporter in Leishmania Parasites are Associated with Cross-resistance to Two Leading Drugs by Distinct Mechanisms.
abstract: Leishmania infantum is an etiological agent of the life-threatening visceral form of leishmaniasis. Liposomal amphotericin B (AmB) followed by a short administration of miltefosine (MF) is a drug combination effective for treating visceral leishmaniasis in endemic regions of India. Resistance to MF can be due to point mutations in the miltefosine transporter (MT). Here we show that mutations in MT are also observed in Leishmania AmB-resistant mutants. The MF-induced MT mutations, but not the AmB induced mutations in MT, alter the translocation/uptake of MF. Moreover, mutations in the MT selected by AmB or MF have a major impact on lipid species that is linked to cross-resistance between both drugs. These alterations include changes of specific phospholipids, some of which are enriched with cyclopropanated fatty acids, as well as an increase in inositolphosphoceramide species. Collectively these results provide evidence of the risk of cross-resistance emergence derived from current AmB-MF sequential or co-treatments for visceral leishmaniasis.
authors.affiliation: Centre 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.
authors.forename: Christopher
authors.initials: C
authors.lastname: Fernandez-Prada
authors.affiliation: Centre 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.
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Vincent
authors.affiliation: Centre 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.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Brotherton
authors.affiliation: Biomedical Sciences Research Complex (BSRC), Schools of Biology & Chemistry, The North Haugh, The University of St. Andrews, United Kingdom.
authors.forename: Mathew
authors.initials: M
authors.lastname: Roberts
authors.affiliation: Centre 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.
authors.forename: Gaétan
authors.initials: G
authors.lastname: Roy
authors.affiliation: Centro de Investigaciones Biológicas (CSIC), Madrid, Spain.
authors.forename: Luis
authors.initials: L
authors.lastname: Rivas
authors.affiliation: Centre 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.
authors.forename: Philippe
authors.initials: P
authors.lastname: Leprohon
authors.affiliation: Biomedical Sciences Research Complex (BSRC), Schools of Biology & Chemistry, The North Haugh, The University of St. Andrews, United Kingdom.
authors.forename: Terry K
authors.initials: TK
authors.lastname: Smith
authors.affiliation: Centre 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.
authors.forename: Marc
authors.initials: M
authors.lastname: Ouellette
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology*; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D018314:Leishmania infantum / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D007896:Leishmaniasis / Q000276:immunology / Q000469:parasitology*; D009154:Mutation; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D015800:Protozoan Proteins; C068538:liposomal amphotericin B; D010767:Phosphorylcholine; C039128:miltefosine; D000666:Amphotericin B; D006180:Proton-Translocating ATPases