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Early Genomic Amplifications in Blood-Stages of ARMD Plasmodium falciparum Acquiring De Novo Drug Resistance

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Plasmodium falciparum Dd2 Plasmodium falciparum

PROVIDER: GSE35950 | GEO | 2013/05/01

SECONDARY ACCESSION(S): PRJNA151983

REPOSITORIES: GEO

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Early Genomic Amplifications in Blood-Stages of ARMD Plasmodium falciparum Acquiring De Novo Drug Resistance [Expression]

Project description:While many molecular changes associated with commonly used antimalarials are known, there remain important questions on how parasites arrive at the correct causal molecular solutions in a haploid genome. We selected for resistance to DSM1, a novel dihydroorotate dehydrogenase (DHODH) inhibitor with a non-biological triazolopyrimidine scaffold, in P. falciparum with the Accelerated Resistance to Multiple Drugs (ARMD) trait. While direct sequencing revealed no mutations in the target DHODH gene, comparative genomic hybridizations from four independently selected DSM1-resistant clones showed a large, single 34-95kb amplification in each clone. Each amplified region always included the DHODH locus. The length of this region and the resulting 2- to 3-fold DHODH copy number increase were verified at the RNA and protein level. DSM1 resistance was stable over several months of in vitro culture. Additional selection at higher DSM1 concentrations caused further gains in CNVs at the DHODH locus. The present system validated DHODH as a key target of the triazolopyrimidine antimalarial, DSM1 and, more importantly, captured large, random CNVs as an early step in the initiation of drug resistance in malaria parasites. This defined system is expected to be valuable for characterizing early, causal molecular steps leading to successful drug resistance

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Early Genomic Amplifications in Blood-Stages of ARMD Plasmodium falciparum Acquiring De Novo Drug Resistance

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