CELLULAR AND MOLECULAR BIOLOGICAL ANALYSES OF NIFURTIMOX RESISTANCE IN TRYPANOSOMA-CRUZI

We induced nifurtimox resistance in both epimastigotes and tissue cult ure-derived trypomastigotes of several Trypanosoma cruzi strains. The magnitude of nifurtimox resistance was strain-dependent. A variety of karyotype changes occurred in the nifurtimox-resistant (NR) strains. C hromosome-specific DNA probes identified karyotype changes common to t he NR strains that were moderately resistant to nifurtimox but not the NR strains that were highly resistant to nifurtimox. A marked increas e in nifurtimox resistance in one NR strain was accompanied by a 100% increase in nuclear DNA mass and a 50% increase in kinetoplast DNA mas s. These data suggest that nifurtimox resistance can be accompanied by a wide spectrum of DNA changes. Both trypanothione reductase and heat -shock proteins may modulate the effects of exposure of T. cruzi to ni furtimox. However, we did not detect qualitative or quantitative diffe rences in these genes or their transcripts between the NR strains and the sensitive strains from which they were derived. An understanding o f the spectrum of diversity in nifurtimox resistance at the cellular a nd molecular levels demonstrated in this report is critical in the dev elopment of drug therapies against Chagas' disease.