Endoperoxide-based compounds: cross-resistance with artemisinins and selection of a Plasmodium falciparum lineage with a K13 non-synonymous polymorphism.
J Antimicrob Chemother
; 73(2): 395-403, 2018 02 01.
Article
em En
| MEDLINE
| ID: mdl-29177421
ABSTRACT
Background:
Owing to the emergence of multiresistant Plasmodium falciparum parasites in Southeast Asia, along with the impressive decrease in the efficacy of the endoperoxide compound artemisinin and of artemisinin-based combination therapies, the development of novel antimalarial drugs or combinations is required. Although several antiplasmodial molecules, such as endoperoxide-based compounds, are in advanced research or development, we do not know whether resistance to artemisinin derivatives might impact the efficacy of these new compounds.Objectives:
To address this issue, the antiplasmodial efficacy of trioxaquines, hybrid endoperoxide-based molecules, was explored, along with their ability to select in vitro resistant parasites under discontinuous and dose-escalating drug pressure.Methods:
The in vitro susceptibilities of artemisinin- and trioxaquine-resistant laboratory strains and recent Cambodian field isolates were evaluated by different phenotypic and genotypic assays.Results:
Trioxaquines tested presented strong cross-resistance with artemisinin both in the artemisinin-resistant laboratory F32-ART5 line and in Cambodian field isolates. Trioxaquine drug pressure over 4 years led to the in vitro selection of the F32-DU line, which is resistant to trioxaquine and artemisinin, similar to the F32-ART lineage. F32-DU whole genome sequencing (WGS) revealed that resistance to trioxaquine was associated with the same non-synonymous mutation in the propeller domain of the K13 protein (M476I) that was found in the F32-ART lineage.Conclusions:
These worrisome results indicate the risk of cross-resistance between artemisinins and endoperoxide-based antiplasmodial drugs in the development of the K13 mutant parasites and question the usefulness of these molecules in the future therapeutic arsenal.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Resistência a Medicamentos
/
Artemisininas
/
Antimaláricos
Limite:
Humans
País/Região como assunto:
Asia
Idioma:
En
Revista:
J Antimicrob Chemother
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
França