Poster Presentation First Malaria World Congress 2018

Chemical Probes to Investigate the Underlying Mechanism of New Permeability Pathways (NPP) in P. falciparum (#425)

Benjamin K Dickerman 1 , Brad E Sleebs 2 , Brendan S Crabb 1 , Paul R Gilson 1
  1. Burnet Institute, Melbourne, VIC, Australia
  2. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

During the first half of the P. falciparum life cycle, the parasite digests haemoglobin to obtain amino acids, and uses nutrients from the erythrocyte cytoplasm. During the second half of the life cycle, rapid growth and replication result in increased metabolic demand that exceeds the intra-erythrocyte reservoir, which must be supplemented with extracellular nutrients. Increased membrane permeability, a phenomenon termed the new permeability pathway (NPP), facilitates uptake of nutrients from the bloodstream to meet this demand, and it has been subsequently shown that blocking this permeability pathway results in parasite death. Therefore this pathway represents an attractive potential drug target. Although this biological phenomenon has been extensively studied for over thirty years, the underlying molecular mechanisms responsible for this effect are poorly understood. We have recently identified two novel inhibitors of this process, which also target the cytochrome bc1 complex. Here we describe the initial refinement of these compounds to generate a specific inhibitor of P. falciparum membrane permeation, and our efforts to use this compound as a tool to identify factors that are required for this effect.