Characterization of alpha-difluoromethylornithine resistant Leishmania donovaniand its susceptibility to other inhibitors of the polyamine biosynthetic pathway

Abstract

The promastigote form ofLeishmania donovaniis sensitive to growth inhibition by DL -α-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase, exhibiting an IC₅₀of 125µM. Exposure of a wild type cell population to gradually increasing concentrations of DL-α-difluoromethylornithine resulted in the selection of a strain of Leishmania, which was capable of proliferating in 5mM DFMO with an IC₅₀value of 10mM. This resistant strain showed increased ornithine decarboxylase activity and higher levels of putrescine. It was sensitive to growth inhibition by bis (benzyl) analogs of spermine and a potent S-adenosylmethionine decarboxylase inhibitor, CGP 40215A. These results indicate the potential value of other inhibitors of the polyamine biosynthetic pathway as therapeutic agents in conditions where ODC inhibitors are ineffective.