Introduction. Emerging resistance to existing anti-malarials demands the discovery of new anti-malarial drugs. Novel anti-malarial targets are a priority to reduce the risk of cross-resistance. Bromodomains bind acetylated lysines, often on histones, and typically they recruit enzymes or transcriptional co-factors to chromatin where they participate in gene regulatory processes. Human bromodomain proteins have been pursued as drug targets for multiple diseases and several inhibitors are in late stage development. Plasmodium falciparum has seven novel bromodomain proteins (PfBDPs) unique to apicomplexan parasites and one that is conserved in eukaryotes but which carries a divergent bromodomain. We propose that these PfBDPs could furnish novel anti-malarial drug targets.
Aims. We aimed to validate the PfBDPs as anti-malarial drug targets and determine their role in parasite growth and development.
Methods. We created inducible knockout/knockdowns (KO/KD) of the PfBDPs and tested these for essentiality for blood and mosquito stage P. falciparum. We further assessed the function of PfBDPs by dissecting their roles in asexual growth and by characterising their associations with chromatin and gene regulation.
Results. Three PfBDPs are essential for asexual blood stage parasite growth and one is required for normal growth, two are required for development in the mosquito. The PfBDPs have diverse and overlapping genomic distributions and functions, with two involved in directly activating genes and three involved in chromatin structure regulation. Multiple PfBDPs are involved in critical processes including the tightly coordinated expression of proteins involved in erythrocyte invasion and sexual development.
Discussion. These results validate multiple PfBDPs as novel anti-malarial drug targets and establish novel functions for PfBDPs in asexual blood stage and mosquito stage parasites.