Genome-wide RNAi screens in African trypanosomes identify the nifurtimox activator NTR and the eflornithine transporter AAT6.


Baker, N; Alsford, S; Horn, D; (2010) Genome-wide RNAi screens in African trypanosomes identify the nifurtimox activator NTR and the eflornithine transporter AAT6. Molecular and biochemical parasitology. ISSN 0166-6851 DOI: https://doi.org/10.1016/j.molbiopara.2010.11.010

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Abstract

To be effective, therapeutic compounds must typically enter target cells and, in some cases, must be concentrated or modified. Thus, uptake and activation mechanisms often form the basis of selectivity against infectious agents. Loss-of-function screens can be used to identify proteins involved in drug uptake and metabolism and may also identify clinically relevant potential resistance mechanisms. We used a genome-scale RNA interference (RNAi) library to identify loss-of-function resistance mechanisms in bloodstream-form Trypanosoma brucei. Nifurtimox-Eflornithine Combination Therapy (NECT) was recently introduced for Human African Trypanosomiasis and we focus on these drugs here. Screens for resistance to nifurtimox and a related drug, benznidazole, identified loss of nitroreductase (NTR) pro-drug activator function. A screen for resistance to the amino-acid analogue, eflornithine, identified loss of amino-acid transporter (AAT6) function. Our results confirm recent findings and suggest that NTR or AAT6 loss-of-function represent major potential mechanisms of resistance to these drugs. Thus, bloodstream-form T. brucei RNAi libraries present a versatile tool for selective genetic screening and for the rapid identification of drug-activation, uptake and potential resistance mechanisms.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
PubMed ID: 21093499
Web of Science ID: 287284800008
URI: http://researchonline.lshtm.ac.uk/id/eprint/2039

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