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
Caio H FrancoCarolina B Moraes

Abstract

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 TcCYP...Continue Reading

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Citations

Jun 19, 2021·Frontiers in Molecular Biosciences·Satabdi Datta Choudhury
Aug 11, 2021·Experimental Parasitology·Pollyanna Álvaro SpósitoVanessa Carla Furtado Mosqueira

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Datasets Mentioned

BETA
AY856083
MH998377
MH998378
MH998379
MH998380
MH998381
MH998382
JQ434483

Methods Mentioned

BETA
PCR
electrophoresis
optical microscopy

Software Mentioned

DUET
BioEdit
Clustal O
DeepView
CLUSTAL
HCA
Expasy
Excel
HyperChem
BLAST

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