Synthetic Biology Strategies for Activating Cryptic BGCs in Streptomyces: Engineering Native and Synthetic Promoters...

The activation of cryptic biosynthetic gene clusters (BGCs) in Streptomyces has emerged as a powerful strategy to uncover novel antibiotics. Recent advances in native and synthetic promoter engineering have enabled precise transcriptional control over silent gene clusters. This review presents a comprehensive overview of constitutive and inducible promoters, both native and synthetic, used in refactoring efforts. It also highlights CRISPR-based activation systems and machine-learning-guided promoter design for BGC activation. Case studies illustrate how these strategies are translated into enhanced metabolite production, particularly in the context of antimicrobial resistance. This review aims to provide a systems-level understanding of promoter tools and their translational implications for natural product discovery.