Resistance to Some but Not Other Dimeric Lindenane Sesquiterpenoid Esters Is Mediated by Mutations in a Plasmodium falciparum Esterase

Joshua H. Butler, Rodrigo P. Baptista, Ana L. Valenciano, Bin Zhou, Jessica C. Kissinger, Patrick K. Tumwebaze, Philip J. Rosenthal, Roland A. Cooper, Jian Min Yue, Maria B. Cassera

Research output: Contribution to journalArticlepeer-review

Abstract

Unique lindenane sesquiterpenoid dimers from Chloranthecae spp. were recently identified with promising in vitro antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, in vitro selection of Plasmodium falciparum resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC50) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered P. falciparum prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC50= 1.6 nM, n = 34) against fresh Ugandan P. falciparum isolates. The analysis of the structure-resistance relationships revealed that in vitro potency of a subset of lindenane sesquiterpenoid dimers was not mediated by PfPARE mutations. Thus, chlorajaponilide C, but not some related compounds, required parasite esterase activity for in vitro potency, and those compounds serve as the foundation for development of potent and selective antimalarials.

Original languageEnglish (US)
Pages (from-to)2994-3003
Number of pages10
JournalACS Infectious Diseases
Volume6
Issue number11
DOIs
StatePublished - Nov 13 2020

Keywords

  • lindenane sesquiterpenoid dimers
  • Malaria Box
  • Pathogen Box
  • PfPARE
  • Plasmodium
  • structure-resistance relationship study

ASJC Scopus subject areas

  • Infectious Diseases

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