posted on 2025-01-21, 11:37authored byJohn M Bennett, Sunil K Narwal, Stephanie Kabeche, Daniel Abegg, Vandana Thathy, Fiona Hackett, Tomas Yeo, Veronica L Li, Ryan Muir, Franco Faucher, Scott Lovell, Michael J Blackman, Alexander Adibekian, Ellen Yeh, David A Fidock, Matthew Bogyo
Malaria, caused by Plasmodium falciparum, remains a significant health burden. One major barrier for developing antimalarial 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 that results in 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 antiparasitic potencies that enabled the identification of therapeutically relevant targets. The active compound kills parasites through a mechanism that is distinct from both SalA and the pan-lipase inhibitor orlistat and shows synergistic killing with orlistat. 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.
Funding
Crick (Grant ID: CC2129, Grant title: Blackman CC2129)