Malaria, caused by mosquito-transmitted Plasmodium spp. parasites, results in >200M cases, >600K deaths, and impacts >10M pregnancies, every year. The related food/water-borne zoonotic Toxoplasma gondii parasite infects >30% of the world’s population at any given time. It is responsible for 190K cases of congenital toxoplasmosis each year, causes ocular toxoplasmosis across the broader population, cerebral infections in the immunocompromised, as well as having a large economic impact on the livestock industry. Both parasites have devastating long-term developmental outcomes, particularly in young children. Parasite resistance to our best antimalarial drugs is spreading whilst toxoplasma drugs have questionable efficacy and safety, highlighting the urgent need to develop safe and effective drugs with novel mechanisms of action. Natural products, representing an incredibly diverse array of chemistry and biological activity, have historically played a key role in drug discovery.
We screened the BioAustralis Discovery Plates Series I, a library of known and rare microbial metabolites mostly sourced from Australian microbes, against P. falciparum and T. gondii. From 812 compounds, 27% across 70 chemical classes inhibited P. falciparum growth and 18% across 54 chemical classes inhibited T. gondii growth, by >80%. A group of lesser-known macrocyclic lactones were further analysed. Compounds with low half maximal inhibitory concentrations were identified in T. gondii and drug-sensitive and multidrug-resistant P. falciparum parasites. These compounds exhibited minimal cytotoxicity against a human cell line, resulting in a large selectivity index, favourable for further development. Stage-specificity in P. falciparum suggested that the compounds inhibit growth and replication early in intraerythrocytic development. Resistance selection in P. falciparum and whole genome sequencing identified several single nucleotide polymorphisms, some of which may point to a mechanism of action.
This library of microbial metabolites presents potent compounds against these disease-causing parasites that may possess novel mechanisms of action worth further investigation.