Novel structural CYP51 mutation in Trypanosoma cruzi associated with multidrug resistance to CYP51 inhibitors and reduced infectivity

International Journal for Parasitology: Drugs and Drug Resistance

卷:13

David C. Warhurst¹  Michael A. Miles²  Hai Le³  Miriam A. Giardini³  Ho Y.A. Au³  Tapan Bhattacharyya³  Lucio H. Freitas-Junior⁴  Eric Chatelain⁵  Rafael Pedro Madeira⁶  Sergio Schenkman⁶  Lavinia M.D. Romera⁶  Carolina B. Moraes⁷  Bruno S. Pascoalino⁸  Ana Claudia Torrecilhas⁹  Caio H. Franco⁹ 

[1] Department of Microbiology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil;

[2] Institut Pasteur Korea, Bundang-gu, Seongnam-si, Gyeonggi-do, Republic of Korea;

[3] Department of Infection Biology, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK;

[4] Department of Microbiology, Immunology and Parasitology, UNIFESP, São Paulo, SP, Brazil;

[5] Department of Pharmaceutical Sciences, Federal University of São Paulo (UNIFESP), Diadema, SP, Brazil;

[6] Drugs for Neglected Diseases Initiative, Geneva, Switzerland;

[7] Laboratório Nacional de Biociências (LNBio), Centro Nacional de Pesquisa em Energia e Materiais (CNPEM), Campinas, SP, Brazil;

关键词: Trypanosoma cruzi;    Drug resistance;    Ravuconazole;    Benznidazole;    CYP51;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown