Changes in lipid composition of phosphonate treated Plasmodium falciparum

Malaria, caused by Plasmodium falciparum, remains a significant health
burden. The barrier to developing anti-malarial drugs is the ability of
the parasite to rapidly generate resistance. We previously demonstrated
that Salinipostin A (SalA), a natural product, potently kills parasites by
inhibiting multiple lipid-metabolizing serine hydrolases, a mechanism with
a low propensity for resistance. Given the difficulty of employing natural
products as therapeutic agents, we synthesized a small library of lipidic
mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional
isomers exhibited divergent anti-parasitic potencies which enabled the
identification of therapeutically relevant targets. We also confirm that
this compound kills parasites through a mechanism that is distinct from
both SalA and the pan-lipase inhibitor, Orlistat. In addition, like SalA,
our compound induces only weak resistance, attributable to mutations in a
single protein involved in multidrug resistance. These data suggest that
mixed alkyl/aryl phosphonates are promising, synthetically tractable
antimalarials with a low propensity to induce resistance.