Harnessing Chimeric Degrader Technologies for Antimicrobial Innovation

Abstract

Infectious diseases remain a major global health threat, with bacterial and viral pathogens responsible for a majority of cases in both humans and animals. While small-molecule inhibitors have been the cornerstones of antimicrobial therapy, their effectiveness is increasingly undermined by the rapid emergence of drug-resistant strains. Targeted protein and RNA degradation represent a novel therapeutic modality that offers key advantages over conventional inhibition-based strategies, including catalytic activity, improved selectivity, the ability to target previously "undruggable" proteins and RNA structures, and the potential to repurpose shelved or discontinued drugs. Building on the clinical success of degraders in oncology, this perspective explores recent advances in targeted degradation approaches, particularly PROTACs, BacPROTACs, homo-BacPROTACs, AUTACs, RIBOTACs, and PINADs, for bacterial and viral infections. We also discuss future perspectives and key design considerations for translating this emerging modality into clinical anti-infective agents.