Protecting the Efficacy of Antimalarial Therapies by Novel Approaches to Suppress the Emergence of Drug Resistance

Dyann Wirth of the Harvard School of Public Health in the U.S. is building a platform to identify combinations of anti-malarial compounds that inhibit the development of drug resistance, which is a major barrier to combatting the disease. Their approach involves predicting how the Plasmodium falciparum malaria parasite will evolve to become resistant to a specific anti-malarial compound, and then designing a second compound that will target these resistant parasites. Since this second drug is not active until resistance to the first drug develops, the population subject to selection is greatly reduced, thereby suppressing the emergence of resistance to the second compound. In Phase I, they demonstrated proof-of-concept of their approach in vitro by combining drugs targeting both the sensitive and the induced resistant form of the known antimalarial drug target P. falciparum dihydroorotate dehydrogenase (PfDHODH), and showing resistance was strongly reduced. In Phase II, they will establish an in vivo platform based on the P. falciparum humanized mouse system, which is similar to the natural human infection, and test more optimal pairings of compounds targeting both PfDHODH and another target enzyme, PfATP4.