An epigenetic antimalarial resistance mechanism involving parasite genes linked to nutrient uptake.
J Biol Chem
; 288(27): 19429-40, 2013 Jul 05.
Article
en En
| MEDLINE
| ID: mdl-23720749
ABSTRACT
Acquired antimalarial drug resistance produces treatment failures and has led to periods of global disease resurgence. In Plasmodium falciparum, resistance is known to arise through genome-level changes such as mutations and gene duplications. We now report an epigenetic resistance mechanism involving genes responsible for the plasmodial surface anion channel, a nutrient channel that also transports ions and antimalarial compounds at the host erythrocyte membrane. Two blasticidin S-resistant lines exhibited markedly reduced expression of clag genes linked to channel activity, but had no genome-level changes. Silencing aborted production of the channel protein and was directly responsible for reduced uptake. Silencing affected clag paralogs on two chromosomes and was mediated by specific histone modifications, allowing a rapidly reversible drug resistance phenotype advantageous to the parasite. These findings implicate a novel epigenetic resistance mechanism that involves reduced host cell uptake and is a worrisome liability for water-soluble antimalarial drugs.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Plasmodium falciparum
/
Resistencia a Medicamentos
/
Proteínas Protozoarias
/
Malaria Falciparum
/
Genes Protozoarios
/
Epigénesis Genética
Límite:
Humans
Idioma:
En
Revista:
J Biol Chem
Año:
2013
Tipo del documento:
Article
País de afiliación:
Estados Unidos