Leishmania gene amplification: a mechanism of drug resistance

Abstract

Leishmania spp. are excellent models for analysing the mechanisms of drug resistance, one of the major barriers to the treatment and control of several major diseases. They may become refractory to drugs as the result of gene amplification. Amplified Leishmania DNA are extrachromosomal, usually circular, and arise from a source chromosome. Several multicopy extrachromosomal DNA have been identified, either spontaneously in unselected stocks or, more commonly, in response to multiple rounds of step-wise increases in drug concentration. R circles, G circles and ODC140-L minichromosomes are extrachromosomal amplifications encoding copies of dihydrofolate reductase-thymidylate synthase, glycosyltransferase, and ornithine decarboxylase, respectively, and conferring resistance to inhibitors of these gene products (methotrexate, tunicamycin and α-difluoromethylornithine, respectively). Another DNA amplification, named the H circle, has been detected in response to several unrelated drugs and confers drug resistance. Leishmania spp. represent a unique model since, even without drug pressure, gene amplifications appear and remain as extrachromosomal circular and linear amplicons. The CD1/LD1 elements, of unknown biological role, arise de novo in cultures in the absence of drug pressure.