Resistance to Some But Not Other Dimeric Lindenane Sesquiterpenoid Esters Is Mediated by Mutations in a Esterase.

Unique lindenane sesquiterpenoid dimers from spp. were recently identified with promising antiplasmodial activity and potentially novel mechanisms of action. To gain mechanistic insights to this new class of natural products, selection of resistance to the most active antiplasmodial compound, chlorajaponilide C, was explored. In all selected resistant clones, the half-maximal effective concentration (EC) of chlorajaponilide C increased >250-fold, and whole genome sequencing revealed mutations in the recently discovered prodrug activation and resistance esterase (PfPARE). Chlorajaponilide C was highly potent (mean EC = 1.6 nM, = 34) against fresh Ugandan isolates. The analysis of the structure-resistance relationships revealed that 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 potency, and those compounds serve as the foundation for development of potent and selective antimalarials.