Phenotypic characterization of Leishmania mexicana pentamidine-resistant promastigotes. Modulation of the resistance during in-vitro developmental life cycle |
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| Affiliation: | 1. Mouse and Human Embryo and Stem Cell Group, University of Cambridge, Department of Physiology, Development and Neuroscience, Downing Street, Cambridge, CB2 3EG, UK;2. Plasticity and Synthetic Embryology Group, California Institute of Technology, Division of Biology and Biological Engineering, 1200 E. California Boulevard, Pasadena, CA, 91125, USA;1. Department of oral Microbiology, São Leopoldo Mandic Institute and Research Center, Campinas, Brazil;2. Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, USA;3. Howard Hughes Medical Institute, California Institute of Technology, Pasadena, USA;1. Department of Zoology, University of Otago, P.O. Box 56, Dunedin 9054, New Zealand;2. ANSES, Agence Nationale de Sécurité Sanitaire de l’Alimentation, de l’Environnement et du Travail - Laboratoire de Ploufragan-Plouzané, Unité Génétique Virale de Biosécurité, Ploufragan, France;3. UMR 1161 Virology ANSES/INRAE/ENVA, ANSES Animal Health Laboratory, 94704 Maisons-Alfort, France |
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| Abstract: | Two clones of Leishmania mexicana resistant to 5 μM (LmR5CL2) and 20 μ M (LmR20CLl) pentamidine, derived from a parental wild-type clone (LmWTCL3) were selected in vitro using a continuons drug pressure protocol. Both resistant clones expressed a cross-resistance to diminazene aceturate. No differences in their in-vitro infectivity for mouse peritoneal macrophages between wild-type and pentamidine-resistant promastigotes were observed. During these experiments, promastigotes of LmR20CL1 derived from intramacrophagic amastigote forms reverted to the pentamidine-sensitive phenotype, unlike the lower resistant ones. In the same way, when a complete developmental sequence of L. mexicana was achieved in axenic cultures, LmR20CL1 promastigotes derived from axenically growing amastigotes expressed an IC50 value close to the wild-type one, whereas resulting LmR5CL2 promastigotes remained pentamidine resistant. This modulation of the chemoresistance during the developmental life cycle could be significant in the transmission of drug-resistant strains by Phlebotominae as well as in basic research to follow drug resistance during the in-vitro and in-vivo life cycle of Leishmania. |
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