Topoisomerase I amino acid substitutions, Gly185Arg and Asp325Glu, confer camptothecin resistance in Leishmania donovani.

ABSTRACT: The antitumor compound camptothecin (CPT) is also recognized for its specific activity against Leishmania donovani topoisomerase I (Topo-I). In consequence, defining CPT resistance mechanisms represents an important strategic tool in the acquisition of a better understanding of its mode of action. In the present study, we selected a single highly resistant L. donovani strain termed LdRCPT.160 by stepwise exposure to CPT. Gene sequencing revealed two single nucleotide mutations in the LdRCPT.160 LdTOP1A gene, resulting in two amino acid substitutions (Gly185Arg and Asp325Glu) in the protein. Moreover, these two substitutions observed in the LdTOP1A protein were correlated with a decreased Topo-I DNA relaxation activity in these resistant parasites. Nevertheless, there was no change in the L

SUBMITTER: Marquis JF 

PROVIDER: S-EPMC1068627 | biostudies-literature | 2005 Apr

REPOSITORIES: biostudies-literature