Malaria, caused by mosquito-transmitted Plasmodium spp. parasites, results in over 200 million cases, over 600,000 deaths, mostly in children under the age of five years, and impacts more than 10 million pregnancies, each year. The related apicomplexan parasite Toxoplasma gondii chronically infects over 30 percent of the world’s population at any given time, and causes 190,000 cases of congenital toxoplasmosis every year, as well as causing a large economic impact on the livestock industry. Both parasites have devastating long-term developmental outcomes. Unfortunately, malaria parasite resistance to our best antimalarial drugs is spreading whilst toxoplasma drugs have safety concerns and poor efficacy, highlighting the urgent need to develop new safe and effective drugs with novel mechanisms of action. Natural products have historically played a key role in drug discovery. Such compounds represent an incredibly diverse array of chemistry and biological activity.
We screened the BioAustralis Discovery Plates, a unique library of 812 known and rare microbial metabolites and few semi-synthetic derivatives sourced mainly from Australian microbes. Using 72-hour assays, 27 and 18 percent of compounds inhibited Plasmodium falciparum and Toxoplasma gondii growth by more than 80 percent, respectively. These compounds belonged to 70 and 54 different chemical classes for P. falciparum and T. gondii, respectively. Compounds resulting in a delayed-death phenotype in P. falciparum were also detected. Compounds with low half maximal inhibitory concentrations were identified, and stage specificity and cell toxicity were examined. Resistance was established in P. falciparum, and whole genome sequencing was performed to investigate the mechanism of action. This library of natural microbial metabolites presents potent compounds that may possess novel mechanisms of action for further investigation.