Mutant PfCRT Can Mediate Piperaquine Resistance in African Plasmodium falciparum With Reduced Fitness and Increased Susceptibility to Other Antimalarials.
J Infect Dis
; 226(11): 2021-2029, 2022 11 28.
Article
em En
| MEDLINE
| ID: mdl-36082431
ABSTRACT
BACKGROUND:
Additional therapeutic strategies could benefit efforts to reverse the recent increase in malaria cases in sub-Saharan Africa, which mostly affects young children. A primary candidate is dihydroartemisinin + piperaquine (DHA + PPQ), which is effective for uncomplicated malaria treatment, seasonal malaria chemoprevention, and intermittent preventive treatment. In Southeast Asia, Plasmodium falciparum parasites acquired PPQ resistance, mediated primarily by mutations in the P falciparum chloroquine resistance transporter PfCRT. The recent emergence in Africa of DHA-resistant parasites creates an imperative to assess whether PPQ resistance could emerge in African parasites with distinct PfCRT isoforms.METHODS:
We edited 2 PfCRT mutations known to mediate high-grade PPQ resistance in Southeast Asia into GB4 parasites from Gabon. Gene-edited clones were profiled in antimalarial concentration-response and fitness assays.RESULTS:
The PfCRT F145I mutation mediated moderate PPQ resistance in GB4 parasites but with a substantial fitness cost. No resistance was observed with the PfCRT G353V mutant. Both edited clones became significantly more susceptible to amodiaquine, chloroquine, and quinine.CONCLUSIONS:
A single PfCRT mutation can mediate PPQ resistance in GB4 parasites, but with a growth defect that may preclude its spread without further genetic adaptations. Our findings support regional use of drug combinations that exert opposing selective pressures on PfCRT.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Plasmodium falciparum
/
Quinolinas
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Malária Falciparum
/
Antimaláricos
Limite:
Child, preschool
/
Humans
País/Região como assunto:
Africa
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article