John M. Bennett, Sunil K. Narwal, Stephanie Kabeche, Daniel Abegg, Fiona Hackett, Tomas Yeo, Veronica L. Li, Ryan K. Muir, Franco F. Faucher, Scott Lovell, Michael J. Blackman, Alexander Adibekian, Ellen Yeh, David A. Fidock, Matthew Bogyo
bioRxiv 2024.01.11.575224; doi: https://doi.org/10.1101/2024.01.11.575224
Malaria, caused by Plasmodium falciparum, remains a significant health burden. A barrier for developing anti-malarial drugs is the ability of the parasite to rapidly generate resistance. We demonstrated that Salinipostin A (SalA), a natural product, 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 library of lipidic mixed alkyl/aryl phosphonates as bioisosteres of SalA. Two constitutional isomers exhibited divergent anti-parasitic potencies which enabled 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. 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 a promising, synthetically tractable anti-malarials with a low-propensity to induce resistance.
