The parasitophorous vacuole nutrient channel is critical for drug access in malaria parasites and modulates the artemisinin resistance fitness cost

Intraerythrocytic malaria parasites proliferate bounded by a parasitophorous vacuolar membrane (PVM). The PVM contains nutrient permeable channels (NPCs) conductive to small molecules, but their relevance for parasite growth for individual metabolites is largely untested. Here we show that growth-relevant levels of major carbon and energy sources pass through the NPCs. Moreover, we find that NPCs are a gate for several antimalarial drugs, highlighting their permeability properties as a critical factor for drug design. Looking into NPC-dependent amino acid transport, we find that amino acid shortage is a reason for the fitness cost in artemisinin-resistant (ARTR) parasites and provide evidence that NPC upregulation to increase amino acids acquisition is a mechanism of ARTR parasites in vitro and in human infections to compensate this fitness cost. Hence, the NPCs are important for nutrient and drug access and reveal amino acid deprivation as a critical constraint in ARTR parasites. [Display omitted] •Drugs and nutrients can reach the intracellular parasite via nutrient-permeable channels•EXP1 activity correlates with NPC-dependent access of solutes to malaria parasites•A shortened amino acid supply has a fitness cost in artemisinin-resistant parasites•Resistant parasites compensate amino acid shortage by increasing NPC activity via EXP1 The vacuolar membrane of malaria parasites harbors nutrient-permeable channels (NPCs) dependent on EXP1 function. Mesén-Ramírez et al. identify which nutrients and drugs require the NPCs to cross this membrane and reveal a critical role of the NPCs when amino acid supply is reduced, such as in artemisinin-resistant parasites.