Targeting deubiquitinating enzymes and ubiquitin pathway modulators to enhance host defense against bacterial infections.

ABSTRACT: The rise of antibiotic-resistant bacterial pathogens poses a critical global health challenge, necessitating innovative therapeutic strategies. This study explores host-targeted therapies by focusing on deubiquitinating enzymes (DUBs), key regulators of the ubiquitin-proteasome system (UPS) that mediate host-pathogen interactions. Using Salmonella-infected macrophages, we screened a UPS-targeted compound library and identified several compounds that enhanced bacterial clearance without affecting host cell viability. Among these, the dual USP25/USP28 inhibitor AZ-1 emerged as one of the top candidates. Transcriptomic profiling revealed infection-induced upregulation of DUBs, particularly USP25, USP46, and OTUD7B. USP25 knockdown significantly reduced intracellular Salmonella,

SUBMITTER: Santelices J 

PROVIDER: S-EPMC12506015 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature