Nitroheterocyclic drug resistance mechanisms in Trypanosoma brucei.

ABSTRACT:

Objectives

The objective of this study was to identify the mechanisms of resistance to nifurtimox and fexinidazole in African trypanosomes.

Methods

Bloodstream-form Trypanosoma brucei were selected for resistance to nifurtimox and fexinidazole by stepwise exposure to increasing drug concentrations. Clones were subjected to WGS to identify putative resistance genes. Transgenic parasites modulating expression of genes of interest were generated and drug susceptibility phenotypes determined.

Results

Nifurtimox-resistant (NfxR) and fexinidazole-resistant (FxR) parasites shared reciprocal cross-resistance suggestive of a common mechanism of action. Previously, a type I nitroreductase (NTR) has been implicated in nitro drug activation. WGS of resistant clones revealed that

SUBMITTER: Wyllie S 

PROVIDER: S-EPMC4743696 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature