Novel structural CYP51 mutation in Trypanosoma cruzi associated with multidrug resistance to CYP51 inhibitors and reduced infectivity
| Autor: | Lavínia Maria Dal'Mas Romera, Caio Haddad Franco, Ana Claudia Torrecilhas, Ho Y.A. Au, Carolina B. Moraes, Hai Le, Bruno dos Santos Pascoalino, Tapan Bhattacharyya, Miriam A. Giardini, Rafael Pedro Madeira, Sergio Schenkman, Lucio H. Freitas-Junior, Eric Chatelain, David C. Warhurst, Michael A. Miles |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Chagas disease Trypanosoma cruzi 030231 tropical medicine Genes Protozoan Clone (cell biology) Drug resistance CYP51 Biology Ravuconazole Article Microbiology lcsh:Infectious and parasitic diseases Cell Line 03 medical and health sciences Sterol 14-Demethylase 0302 clinical medicine medicine Animals Pharmacology (medical) lcsh:RC109-216 Chagas Disease Nifurtimox Pharmacology Triazoles biology.organism_classification medicine.disease Trypanocidal Agents Drug Resistance Multiple Multiple drug resistance Thiazoles 030104 developmental biology Infectious Diseases Benznidazole 14-alpha Demethylase Inhibitors Nitroimidazoles Mutation Parasitology medicine.drug |
| Zdroj: | International Journal for Parasitology: Drugs and Drug Resistance International Journal for Parasitology: Drugs and Drug Resistance, Vol 13, Iss, Pp 107-120 (2020) |
| ISSN: | 2211-3207 |
| Popis: | 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. Graphical abstract Image 1 Highlights • A ravuconazole-resistant T. cruzi clone presented reduced in vitro and in vivo fitness. • The ravuconazole-resistant clone presented cross-resistance to other CYP51 inhibitors. • There was no cross-resistance to benznidazole and nifurtimox. • Resistance is associated with a novel structural mutation in the TcCYP51 protein. |
| Databáze: | OpenAIRE |
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