School of Medicine, Deakin University, Geelong, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
Katheryn Hjerrild
School of Medicine, Deakin University, Geelong, Australia
Tess R Malcolm
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; Centre to Impact AMR, Monash University, Melbourne, Australia
Natalie B Vinh
Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
Chaille T Webb
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; Centre to Impact AMR, Monash University, Melbourne, Australia
Clare Holmes
CSIRO Australian Centre for Disease Preparedness, Geelong, Australia
Christopher A MacRaild
Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
School of Medicine, Deakin University, Geelong, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia
Willy W Suen
CSIRO Australian Centre for Disease Preparedness, Geelong, Australia
School of Medicine, Deakin University, Geelong, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia
Biomedicine Discovery Institute and Department of Microbiology, Monash University, Clayton, Australia; Centre to Impact AMR, Monash University, Melbourne, Australia
School of Medicine, Deakin University, Geelong, Australia; The Institute for Mental and Physical Health and Clinical Translation, Deakin University, Geelong, Australia
Plasmodium falciparum, the causative agent of malaria, remains a global health threat as parasites continue to develop resistance to antimalarial drugs used throughout the world. Accordingly, drugs with novel modes of action are desperately required to combat malaria. P. falciparum parasites infect human red blood cells where they digest the host’s main protein constituent, hemoglobin. Leucine aminopeptidase PfA-M17 is one of several aminopeptidases that have been implicated in the last step of this digestive pathway. Here, we use both reverse genetics and a compound specifically designed to inhibit the activity of PfA-M17 to show that PfA-M17 is essential for P. falciparum survival as it provides parasites with free amino acids for growth, many of which are highly likely to originate from hemoglobin. We further show that loss of PfA-M17 results in parasites exhibiting multiple digestive vacuoles at the trophozoite stage. In contrast to other hemoglobin-degrading proteases that have overlapping redundant functions, we validate PfA-M17 as a potential novel drug target.
