Beyond Clavulanic Acid biosynthesis: Exploring the broad regulatory impact of BldD in Streptomyces clavuligerus ATCC 27064.

Abstract

BldD is a global regulator of morphological development in Streptomyces, usually acting as a repressor of aerial mycelium formation. However, its role in metabolism and secondary biosynthesis in the wild-type strain Streptomyces clavuligerus remains poorly understood. In this study, we constructed a S. clavuligerus strain overexpressing bldD and compared it with the empty vector control strain during fermentation in soy protein isolate medium. For this, transcriptomic analyses were performed at 24 h and 72 h. We observed that BldD overexpression reduced CA production and repressed genes involved in cephamycin C biosynthesis, including lat and the pathway regulator ccaR. In contrast, genes associated with terpene biosynthesis, phage tail-like particles (CIS), and aerial mycelium formation (bldN, bldM, chaplins) were upregulated. These changes suggest that BldD may directly and indirectly redirects metabolic flux away from β-lactam biosynthesis while promoting morphological differentiation, alternative defense systems and a potential link with GlcNAc metabolism. By repressing β-lactam pathways and enhancing CIS and terpene gene expression, BldD shifts cellular priorities toward morphological development and ecological defense, underscoring species-specific differences from the well-studied model Streptomyces coelicolor. These results greatly contribute to the understanding of the regulatory mechanisms involved in CA biosynthesis.