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1.
Commun Biol ; 5(1): 274, 2022 03 28.
Article in English | MEDLINE | ID: mdl-35347215

ABSTRACT

The emergence and spread of artemisinin-resistant Plasmodium falciparum, first in the Greater Mekong Subregion (GMS), and now in East Africa, is a major threat to global malaria elimination ambitions. To investigate the artemisinin resistance mechanism, transcriptome analysis was conducted of 577 P. falciparum isolates collected in the GMS between 2016-2018. A specific artemisinin resistance-associated transcriptional profile was identified that involves a broad but discrete set of biological functions related to proteotoxic stress, host cytoplasm remodelling, and REDOX metabolism. The artemisinin resistance-associated transcriptional profile evolved from initial transcriptional responses of susceptible parasites to artemisinin. The genetic basis for this adapted response is likely to be complex.


Subject(s)
Antimalarials , Malaria, Falciparum , Parasites , Animals , Antimalarials/pharmacology , Antimalarials/therapeutic use , Artemisinins , Drug Resistance/genetics , Malaria, Falciparum/drug therapy , Malaria, Falciparum/parasitology , Plasmodium falciparum
2.
Antimicrob Agents Chemother ; 65(12): e0112121, 2021 11 17.
Article in English | MEDLINE | ID: mdl-34516247

ABSTRACT

Increasing resistance in Plasmodium falciparum to artemisinins and their artemisinin combination therapy (ACT) partner drugs jeopardizes effective antimalarial treatment. Resistance is worst in the Greater Mekong subregion. Monitoring genetic markers of resistance can help to guide antimalarial therapy. Markers of resistance to artemisinins (PfKelch mutations), mefloquine (amplification of P. falciparum multidrug resistance-1 [PfMDR1]), and piperaquine (PfPlasmepsin2/3 amplification and specific P. falciparum chloroquine resistance transporter [PfCRT] mutations) were assessed in 6,722 P. falciparum samples from Vietnam, Lao People's Democratic Republic (PDR), Cambodia, Thailand, and Myanmar between 2007 and 2019. Against a high background prevalence of PfKelch mutations, PfMDR1 and PfPlasmepsin2/3 amplification closely followed regional drug pressures over time. PfPlasmepsin2/3 amplification preceded piperaquine resistance-associated PfCRT mutations in Cambodia and reached a peak prevalence of 23/28 (82%) in 2015. This declined to 57/156 (38%) after first-line treatment was changed from dihydroartemisinin-piperaquine to artesunate-mefloquine (ASMQ) between 2014 and 2017. The frequency of PfMDR1 amplification increased from 0/293 (0%) between 2012 and 2017 to 12/156 (8%) in 2019. Amplification of PfMDR1 and PfPlasmepsin2/3 in the same parasites was extremely rare (4/6,722 [0.06%]) and was dispersed over time. The mechanisms conferring mefloquine and piperaquine resistance may be counterbalancing. This supports the development of ASMQ plus piperaquine as a triple artemisinin combination therapy.


Subject(s)
Antimalarials , Malaria, Falciparum , Antimalarials/pharmacology , Antimalarials/therapeutic use , Drug Resistance/genetics , Drug Resistance, Multiple/genetics , Genetic Markers , Humans , Longitudinal Studies , Malaria, Falciparum/drug therapy , Multidrug Resistance-Associated Proteins/genetics , Plasmodium falciparum/genetics , Protozoan Proteins/genetics , Protozoan Proteins/therapeutic use
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