From Epigenetic Regulation to Protein Degradation: Emerging Strategies for Anti-Infective Drug Discovery

Infectious diseases remain a major global health challenge, driven by antimicrobial resistance, pathogen persistence, and the limited integration of mechanistically innovative therapeutic approaches. Emerging evidence indicates that epigenetic regulation is fundamental to host–pathogen interactions, influencing transcriptional programmes associated with virulence, immune evasion, stress adaptation, and phenotypic plasticity. In organisms such as bacteria, parasites, and intracellular pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, chromatin-associated regulators and DNA-modifying enzymes have been identified as dosage-sensitive determinants of infection outcomes. Traditional strategies focus primarily on occupancy-driven enzymatic inhibition. In contrast, targeted protein degradation (TPD) introduces an event-driven pharmacological paradigm in which transient ligand engagement triggers sustained depletion of regulatory proteins. Platforms such as proteolysis-targeting chimeras (PROTACs) and BacPROTACs exemplify the ability to exploit host and pathogen proteolytic systems, thereby expanding the druggable proteome beyond conventional small-molecule targets. This review examines the relationship between epigenetic regulation and pathogen survival, highlights recent advances in degradation technologies, and discusses conceptual and translational challenges in implementing TPD in antimicrobial and antiparasitic drug discovery.