Additional PfCRT mutations driven by selective pressure for improved fitness can result in the loss of piperaquine resistance and altered Plasmodium falciparum physiology

Our study leverages gene editing techniques in asexual blood stage parasites to profile novel mutations in mutant PfCRT, an important mediator of piperaquine resistance, which developed in Southeast Asian field isolates or in parasites cultured for long periods of time. We provide evidence that incr...

Full description

Saved in:
Bibliographic Details
Published inmBio Vol. 15; no. 1; p. e0183223
Main Authors Hagenah, Laura M, Dhingra, Satish K, Small-Saunders, Jennifer L, Qahash, Tarrick, Willems, Andreas, Schindler, Kyra A, Rangel, Gabriel W, Gil-Iturbe, Eva, Kim, Jonathan, Akhundova, Emiliya, Yeo, Tomas, Okombo, John, Mancia, Filippo, Quick, Matthias, Roepe, Paul D, Llinás, Manuel, Fidock, David A
Format Journal Article
LanguageEnglish
Published United States American Society for Microbiology 16.01.2024
Subjects
Animals
Antimalarials - pharmacology
Chloroquine - pharmacology
Drug Resistance - genetics
drug resistance evolution
Editor’s Pick
fitness
malaria
Malaria, Falciparum - parasitology
Mutation
Parasites
Parasitology
PfCRT
Piperazines
Plasmodium falciparum
Protozoan Proteins - chemistry
Protozoan Proteins - genetics
Quinolines - chemistry
Quinolines - pharmacology
Research Article
Plasmodium falciparum
PfCRT
malaria
fitness
drug resistance evolution
Online AccessGet full text

Cover

More Information
Summary:Our study leverages gene editing techniques in asexual blood stage parasites to profile novel mutations in mutant PfCRT, an important mediator of piperaquine resistance, which developed in Southeast Asian field isolates or in parasites cultured for long periods of time. We provide evidence that increased parasite fitness of these lines is the primary driver for the emergence of these PfCRT variants. These mutations differentially impact parasite susceptibility to piperaquine and chloroquine, highlighting the multifaceted effects of single point mutations in this transporter. Molecular features of drug resistance and parasite physiology were examined in depth using proteoliposome-based drug uptake studies and peptidomics, respectively. Energy minimization calculations, showing how these novel mutations might impact the PfCRT structure, suggested a small but significant effect on drug interactions. This study reveals the subtle interplay between antimalarial resistance, parasite fitness, PfCRT structure, and intracellular peptide availability in PfCRT-mediated parasite responses to changing drug selective pressures.
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
The authors declare no conflict of interest.
ISSN:2150-7511
2150-7511
DOI:10.1128/mbio.01832-23