title: Comparative Fitness of a Parent Leishmania donovani Clinical Isolate and Its Experimentally Derived Paromomycin-Resistant Strain.
abstract: Paromomycin has recently been introduced for the treatment of visceral leishmaniasis and emergence of drug resistance can only be appropriately judged upon its long term routine use in the field. Understanding alterations in parasite behavior linked to paromomycin-resistance may be essential to assess the propensity for emergence and spread of resistant strains. A standardized and integrated laboratory approach was adopted to define and assess parasite fitness of both promastigotes and amastigotes using an experimentally induced paromomycin-resistant Leishmania donovani strain and its paromomycin-susceptible parent wild-type clinical isolate. Primary focus was placed on parasite growth and virulence, two major components of parasite fitness. The combination of in vitro and in vivo approaches enabled detailed comparison of wild-type and resistant strains for which no differences could be demonstrated with regard to promastigote growth, metacyclogenesis, in vitro infectivity, multiplication in primary peritoneal mouse macrophages and infectivity for Balb/c mice upon infection with 2 x 107 metacyclic promastigotes. Monitoring of in vitro intracellular amastigote multiplication revealed a consistent decrease in parasite burden over time for both wild-type and resistant parasites, an observation that was subsequently also confirmed in a larger set of L. donovani clinical isolates. Though the impact of these findings should be further explored, the study results suggest that the epidemiological implications of acquired paromomycin-resistance may remain minimal other than the loss of one of the last remaining drugs effective against visceral leishmaniasis.
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hendrickx
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Leemans
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium.
authors.forename: Annelies
authors.initials: A
authors.lastname: Mondelaers
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Suman
authors.initials: S
authors.lastname: Rijal
authors.affiliation: BP Koirala Institute of Health Sciences, Dharan, Nepal.
authors.forename: Basudha
authors.initials: B
authors.lastname: Khanal
authors.affiliation: Molecular Parasitology Unit, Institute of Tropical Medicine Antwerp, Antwerp, Belgium; Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Dujardin
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Delputte
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium.
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.affiliation: Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Antwerp, Belgium.
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D004351:Drug Resistance; D005260:Female; D056084:Genetic Fitness; D066298:In Vitro Techniques; D007893:Leishmania donovani / Q000187:drug effects / Q000302:isolation & purification / Q000502:physiology*; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D010303:Paromomycin / Q000494:pharmacology*
chemical_list: D000981:Antiprotozoal Agents; D010303:Paromomycin