Genomic and biological features of Plasmodium falciparum resistance against antimalarial endoperoxide N-89

Masayuki Morita, Kosuke Hayashi, A. Sato, A. Hiramoto, O. Kaneko, Rena Isogawa, Yuji Kurosaki, Shin-ichi Miyoshi, Kyung Soo Chang, Yusuke Wataya, Hye-Sook Kim

Research output: Contribution to journalArticle

Abstract

Drug resistance of malaria parasites remains a problem affecting antimalarial treatment and control of the disease. We previously synthesized an antimalarial endoperoxide, N-89, having high antimalarial effects in vitro and in vivo. In this study we seek to understand the resistant mechanism against N-89 by establishing a highly N-89-resistant clone, named NRC10H, of the Plasmodium falciparum FCR-3 strain. We describe gene mutations in the parent FCR-3 strain and the NRC10H clone using whole-genome sequencing and subsequently by expression profiling using quantitative real-time PCR. Seven genes related to drug resistance, proteolysis, glycophosphatidylinositol anchor biosynthesis, and phosphatidylethanolamine biosynthesis exhibited a single amino acid substitution in the NRC10H clone. Among these seven genes, the multidrug resistance protein 2 (mdr2) variant A532S was found only in NRC10H. The genetic status of the P. falciparum endoplasmic reticulum-resident calcium binding protein (PfERC), a potential target of N-89, was similar between the NRC10H clone and the parent FCR-3 strain. These findings suggest that the genetic alterations of the identified seven genes, in particular mdr2, in NRC10H could give rise to resistance of the antimalarial endoperoxide N-89.

Original languageEnglish
Article number144016
JournalGene
Volume716
DOIs
Publication statusPublished - Oct 20 2019

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Keywords

  • Antimalarial endoperoxide
  • Drug resistance
  • Malaria
  • N-89
  • Whole-genome sequencing

ASJC Scopus subject areas

  • Genetics

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