期刊
INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE
卷 13, 期 -, 页码 107-120出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ijpddr.2020.06.001
关键词
Trypanosoma cruzi; Drug resistance; Ravuconazole; Benznidazole; CYP51
资金
- DNDi
- Institut Pasteur Korea (IPK)
- Reconstruction Credit Institution-Federal Ministry of Education and Research (KfWBMBF)/Germany
- Medecins Sans Frontieres (Doctors without Borders)/International
- Department for International Development (DFID), UK
- Directorate-General for International Cooperation (DGIS), The Netherlands
- Swiss Agency for Development and Cooperation (SDC)
- Korean government (MSIP), Gyeonggi-do [2007-00559]
- KISTI
Ergosterol biosynthesis inhibitors, such as posaconazole and ravuconazole, have been proposed as drug candidates for Chagas disease, a neglected infectious tropical disease caused by the protozoan parasite Trypanosoma cruzi. To understand better the mechanism of action and resistance to these inhibitors, a clone of the T. cruzi Y strain was cultured under intermittent and increasing concentrations of ravuconazole until phenotypic stability was achieved. The ravuconazole-selected clone exhibited loss in fitness in vitro when compared to the wild-type parental clone, as observed in reduced invasion capacity and slowed population growth in both mammalian and insect stages of the parasite. In drug activity assays, the resistant clone was above 300-fold more tolerant to ravuconazole than the sensitive parental clone, when the half-maximum effective concentration (EC50) was considered. The resistant clones also showed reduced virulence in vivo, when compared to parental sensitive clones. Cross-resistance to posaconazole and other CYP51 inhibitors, but not to other antichagasic drugs that act independently of CYP51, such as benznidazole and nifurtimox, was also observed. A novel amino acid residue change, T297M, was found in the TcCYP51 gene in the resistant but not in the sensitive clones. The structural effects of the T297M, and of the previously described P355S residue changes, were modelled to understand their impact on interaction with CYP51 inhibitors.
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