title: Oral putrescine restores virulence of ornithine decarboxylase-deficient Leishmania donovani in mice.
abstract: Administration of putrescine as a 1% solution in the drinking water ameliorated the profound loss of virulence exhibited by ornithine decarboxylase (ODC) deficient Leishmania donovani in mice. Furthermore, supplying α-difluoromethylornithine, an ODC inhibitor, at 2% in the drinking water reduced but did not eliminate infection with wild type L. donovani in the mouse model. Taken collectively, these findings: (1) demonstrate that oral putrescine can access the phagolysosome of macrophages in which the parasite resides in mice; (2) establish that the loss of virulence due to the Δodc lesion is a consequence of the inability of the mutant parasite to synthesize sufficient polyamines de novo; (3) imply that the L. donovani amastigote cannot access host polyamines in sufficient amounts for survival and growth; (4) and validate ODC as a drug target, although oral administration of DFMO is an unlikely therapeutic paradigm for visceral leishmaniasis.
authors.affiliation: Department of Biochemistry and Molecular Biology, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, OR 97239-3098, USA.
authors.forename: Tamara
authors.initials: T
authors.lastname: Olenyik
authors.forename: Caslin
authors.initials: C
authors.lastname: Gilroy
authors.forename: Buddy
authors.initials: B
authors.lastname: Ullman
mesh_terms: D000284:Administration, Oral; D000818:Animals; D004195:Disease Models, Animal; D000518:Eflornithine / Q000494:pharmacology* / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D007893:Leishmania donovani / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000469:parasitology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy; D030781:Organisms, Genetically Modified / Q000235:genetics / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D065108:Ornithine Decarboxylase Inhibitors; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism; D011700:Putrescine / Q000378:metabolism / Q000494:pharmacology; D014774:Virulence / Q000187:drug effects* / Q000235:genetics*; D014867:Water / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D065108:Ornithine Decarboxylase Inhibitors; D014867:Water; D009955:Ornithine Decarboxylase; D011700:Putrescine; D000518:Eflornithine