Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
Summary
The widespread use of chloroquine to treat
P
lasmodium falciparum
infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant
PfCRT
. These haplotypes have encountered drug pressure and within‐host competition with wild‐type drug‐sensitive parasites. To examine these selective forces
in vitro
, we genetically engineered
P
. falciparum
to express geographically diverse
PfCRT
haplotypes. Variant alleles from the
P
hilippines (
PH1
and
PH2
, which differ solely by the
C72S
mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates
in vitro
. Of the two,
PH2
showed higher
IC
50
values, contrasting with reduced growth. Furthermore, a highly mutated
pfcrt
allele from
C
ambodia (
C
am734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild‐type
pfcrt
in co‐culture competition assays. These three alleles mediated cross‐resistance to amodiaquine, an antimalarial drug widely used in
A
frica. Each allele, along with the globally prevalent
Dd2
and
7G8
alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first‐line artemisinin‐based combination therapy. These data reveal ongoing region‐specific evolution of
PfCRT
that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine‐resistant malaria.
Sprache
Englisch
Identifikatoren
ISSN: 0950-382X
eISSN: 1365-2958
DOI: 10.1111/mmi.13035
Titel-ID: cdi_crossref_primary_10_1111_mmi_13035
Format
–
Weiterführende Literatur
Empfehlungen zum selben Thema automatisch vorgeschlagen von bX