Articles

Antimicrobial resistance is now among the leading causes of death worldwide, yet the clinical antibacterial pipeline remains critically thin. Genome sequencing has revealed that Streptomyces species carry far more biosynthetic gene clusters than the metabolites they express, indicating a large reservoir of cryptic antibiotics that remains transcriptionally silent under laboratory conditions. This review examines how CRISPR-based genome and transcriptome engineering can be directed at the regulatory layer that keeps these clusters dormant. We summarise the architecture of cluster-situated and global regulators, compare CRISPR-Cas9, base-editing and CRISPR interference or activation strategies for promoter replacement and repressor removal, and consider reported yields, off-target risks and scale-up constraints. Finally, we place cryptic-metabolite discovery within a One Health framework, in which human, veterinary and environmental antibiotic use jointly shape resistance. Coupling regulatory rewiring with stewardship offers a realistic route to replenishing the antibacterial pipeline.