Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei.
Melaminophenyl arsenical drugs are a mainstay of chemotherapy against late-stage African sleeping sickness, but drug resistance is increasingly prevalent. We describe here the characterization of two genes encoding putative metal-thiol conjugate transporters from Trypanosoma brucei. The two proteins, TbMRPA and TbMRPE, were each overexpressed in trypanosomes, with or without co-expression of two key enzymes in trypanothione biosynthesis, ornithine decarboxylase and gamma-glutamyl-cysteine synthetase. Overexpression of gamma-glutamyl-cysteine synthetase resulted in a twofold increase in cellular trypanothione, whereas overexpression of ornithine decarboxylase had no effect on the trypanothione level. The overexpression of TbMRPA resulted in a 10-fold increase in the IC50 of melarsoprol. The overexpression of the trypanothione biosynthetic enzymes alone gave two- to fourfold melarsoprol resistance, but did not enhance resistance caused by MRPA. Overexpression of TbMRPE had little effect on susceptibility to melarsoprol but did give two- to threefold resistance to suramin.[1]References
- Overexpression of the putative thiol conjugate transporter TbMRPA causes melarsoprol resistance in Trypanosoma brucei. Shahi, S.K., Krauth-Siegel, R.L., Clayton, C.E. Mol. Microbiol. (2002) [Pubmed]
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