Dual plasmepsin IX and X inhibitors are refractory to development of resistance in malaria Plasmodium falciparum
The potential for the development of drug resistance against plasmepsin X (PMX)-selective inhibitors and dual plasmepsin IX/X (PMIX/X) inhibitors was investigated in Plasmodium falciparum. A series of PMX-selective (WM4, WM76, WM92) and PMIX/X dual inhibitors (WM382, WM09, WM42) were characterised for potency against parasite growth and enzyme inhibition. In vitro selection experiments revealed a high barrier to resistance for all compounds; however, decreased sensitivity to PMX-selective inhibitors could be selected. Resistance mechanisms involved pmx gene amplification and point mutations (I363L, D245N, S359P, S315P) that alter inhibitor binding.