Relevance Malaria is one of the most threatening infectious diseases, placing almost half of the world-population at risk, and is responsible for nearly 1 million deaths annually. Despite intensive research, no effective vaccine is available and resistance is spreading against the current, and only available, line of medication. Therefore, new drug-targets and novel strategies to fight this disease are urgently required. Histone deacetylase (HDAC) inhibitors, successfully used in cancer-therapy, pose anti-malarial activity against in vitro human and in vivo rodent malaria infections. However, their exact targets and the molecular underpinning of their anti-malarial effect so-far remain completely unspecified, but are essential to improve therapeutic efficacy. Project HDACs are prime enzymes in epigenetic regulation of gene expression and genome-organization. In eukaryotes, they function in large multi-protein complexes, and when targeted to their sites-of-action orchestrate transcriptional repression via their various epigenetic activities. However, the composition of the presumed mega-dalton HDAC-complexes in malaria parasites is completely unknown. I aim to: 1. Characterize the HDAC-(sub)complexes in the deadly human malaria parasite Plasmodium falciparum utilising the latest proteomic approaches, 2. Identify the genome-wide localization of these various (sub)complexes using state-of-the-art next-generation-sequencing, 3. Identify chemical compounds that specifically inhibit the catalytic HDAC-activity or complex-recruitment employing high-tech chemoproteomics. By means of this combined approach of complex-characterization and ?epidrug? identification, I aim to uncover Plasmodium(-specific) epigenetic mechanisms and identify promising targets for rational-based drug design. Innovation This is a timely, ambitious and ground-breaking project, which will most likely result in: - Elucidation of the composition of HDAC-(sub)complexes - Genome-wide ChIP-seq localization, which I have pioneered for Plasmodium, of HDAC-complexes - Testing of candidate-epidrugs on physiologically relevant native, mega-dalton protein complexes (instead of physiologically less representative singular recombinant HDAC proteins) as a prelude to novel therapy - Adaptation of state-of-the-art proteomics & top-notch chemoproteomic approaches to malaria research.