School of Infection & Immunity

Dr Mukul Rawat

Title: Targeting the PfGCN5 bromodomain reveals a novel link between epigenetic regulation and mitochondrial function in Plasmodium falciparum

Synopsis: Epigenetic modifiers play a critical role in gene regulation by modifying histone residues. Due to their essential functions, these proteins have been extensively studied to understand their biological roles and as potential drug targets in various diseases. In Plasmodium falciparum, PfGCN5 is a key epigenetic regulator involved in invasion, virulence gene expression, stress adaptation, and artemisinin resistance. In this study, we investigated whether the bromodomain of PfGCN5 can be therapeutically targeted. Bromodomains bind acetylated lysine residues on histones to regulate transcription. Using conditional knockdown approaches, we demonstrate that the PfGCN5 bromodomain is essential for parasite survival during the blood stage. Using L45 as a tool compound, previously identified to bind the PfGCN5 bromodomain, we evaluated both its antimalarial potential and mechanisms of resistance. In vitro evolution of drug resistance followed by whole-genome sequencing unexpectedly identified point mutations in a mitochondrial carrier protein (PfAMC3) and a previously uncharacterised putative kinase (PfMIR1). Interestingly, L45 resistance mutations in PfAMC3 result in hypersensitivity to mitochondrial inhibitors such as atovaquone, DSM1, and myxothiazol, suggesting altered mitochondrial function. The putative kinase PfMIR1, which is specific to apicomplexan parasites, also contributes to resistance against mitochondrial inhibitors. Metabolomic profiling further revealed accumulation of dUMP following L45 treatment, indicating disruption of pyrimidine metabolism. Together, these findings highlight the PfGCN5 bromodomain as a promising antimalarial drug target and reveal a previously unrecognised link between epigenetic regulation and mitochondrial metabolism, providing new insights into resistance mechanisms.

Bio: Dr Rawat completed his integrated MS–PhD at the Indian Institute of Science Education and Research (IISER), Pune, India, where he worked with Dr Krishanpal Karmodiya on malaria epigenetics, focusing on stress adaptation in Plasmodium parasites. Following his PhD, he joined Prof. Marcus Lee’s laboratory at the Wellcome Sanger Institute in 2020, where his research centred on understanding drug resistance mechanisms in Plasmodium falciparum and identifying novel epigenetic drug targets. In 2023, he moved with the Lee lab to the University of Dundee, where he continues his postdoctoral research.

First published: 8 September 2026

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