Oral Presentation First Malaria World Congress 2018

Biochemical screens reveal that a high proportion of antimalarial drug candidates from phenotypic screens target PfATP4 (#16)

Adelaide S.M. Dennis 1 , James E.O. Rosling 1 , Adele M. Lehane 1 , Kiaran Kirk 1
  1. Research School of Biology, Australian National University, Canberra, ACT, Australia

Whole cell ‘phenotypic’ screening of chemical libraries has led to the identification of large numbers of compounds that inhibit the growth of asexual blood-stage Plasmodium falciparum parasites.  The Medicines for Malaria Venture (MMV) has made available several chemically diverse sets of such compounds.  We have adapted a series of biochemical/physiological assays to a 96-well plate format and used these to screen the MMV antimalarial compound collections.  Some 7-9% of the antimalarials identified in phenotypic screens show the same characteristics:  they cause an increase in parasite Na+ levels, an increase in the parasite’s cytosolic pH, and an increase in parasite volume;  they inhibit the Na+ ATPase activity associated with the parasite membrane;  and they have reduced efficacy against parasites with mutations in PfATP4, a putative plasma membrane Na+/H+ pump.  The data are consistent with 7-9% of the antimalarials identified in phenotypic screens inhibiting PfATP4.  The biochemical/physiological assays used here provide a ready means of identifying PfATP4 inhibitors.