Efficient identification of antimalarials with novel mechanism of action via multi-sample transcriptomic profiling

Malaria poses a significant health burden to endemic countries, necessitating the development of new antimalarials with novel mechanisms of action to combat emerging drug resistance. However, target identification methods for antimalarial compounds selected through phenotypic screening are currently limited, which has been a major obstacle in the field of antimalarial drug discovery. Here, we aim to address this need using perturbation transcriptomics to efficiently select antimalarial compounds targeting new pathways or molecules. The method involves comparing the transcriptomic changes by drug perturbation in the asexual blood stage of the malaria parasite Plasmodium falciparum. Using this method, we identified several compounds that exhibited distinct transcriptomic profiling from a diverse set of antimalarials with known modes of action, indicating their potential to target different pathways. In addition, we successfully identified a novel histone deacetylase inhibitor using this approach and chemogenetically validated its target through in vitro evolution. These results highlight the effectiveness of this platform in accelerating antimalarial drug discovery.