A key developmental regulator controls the synthesis of the antibiotic erythromycin in Saccharopolyspora erythraea

Abstract

Saccharopolyspora erythraea makes erythromycin, an antibiotic commonly used in human medicine. Unusually, the erythromycin biosynthetic (ery) cluster lacks a pathway-specific regulatory gene. We isolated a transcriptional regulator of the ery biosynthetic genes from S. erythraea and found that this protein appears to directly link morphological changes caused by impending starvation to the synthesis of a molecule that kills other bacteria, i.e., erythromycin. DNA binding assays, liquid and affinity chromatography, MALDI-MS analysis, and de novo sequencing identified this protein (M r ‫؍‬ 18 kDa) as the S. erythraea ortholog of BldD, a key regulator of development in Streptomyces coelicolor. Recombinant S. erythraea BldD bound to all five regions containing promoters in the ery cluster as well as to its own promoter, the latter with an order-of-magnitude stronger than to the ery promoters. Deletion of bldD in S. erythraea decreased the erythromycin titer in a liquid culture 7-fold and blocked differentiation on a solid medium. Moreover, an industrial strain of S. erythraea with a higher titer of erythromycin expressed more BldD than a wild-type strain during erythromycin synthesis. Together, these results suggest that BldD concurrently regulates the synthesis of erythromycin and morphological differentiation. The ery genes are the first direct targets of a BldD ortholog to be identified that are positively regulated.cell differentiation ͉ secondary metabolites ͉ BldD

Regulation of Sporangium Formation by BldD in the Rare Actinomycete Actinoplanes missouriensis

“…Additionally, three of the four genes that appeared to be activated by AmBldD have their respective AmBldD-binding sites at positions Ϫ53, Ϫ59, and Ϫ74, which are appropriate positions for being bound by a typical transcriptional activator. As suggested elsewhere (11,15,20), it is possible that BldD and its orthologues also function as transcriptional activators for some genes.…”

Carbon source regulation of antibiotic production

“…154 In S. erythraea, the erythromycin biosynthetic cluster lacks a regulatory gene. 155 However, a 17.7-kDa bldD ortholog has recently been described, which positively regulates all promoters in the erythromycin production cluster, suggesting the existence of a transcriptional activator of the ery gene cluster. 155 In S. coelicolor, BldD negatively regulates the expression of key developmental genes.…”

“…155 However, a 17.7-kDa bldD ortholog has recently been described, which positively regulates all promoters in the erythromycin production cluster, suggesting the existence of a transcriptional activator of the ery gene cluster. 155 In S. coelicolor, BldD negatively regulates the expression of key developmental genes. 156 bldD mutants pleiotropically affect both formation of aerial hyphae and antibiotic production in this microorganism.…”

“…157 Similarly, S. erythraea bldD mutants produce a bald phenotype and sevenfold less erythromycin than the S. erythraea wild-type strain (NRRL2338). 155 Nocardia. Bacteria from the genus nocardia produce a wide variety of secondary metabolites.…”

Actinoplanes Swims into the Molecular Age

“…Bearing this in mind, it is important to note that in another filamentous actinomycete, Saccharopolyspora erythraea, BldD not only controls morphological differentiation, it also directly regulates the expression of the gene cluster that specifies the biosynthesis of the clinically important antibiotic erythromycin (32,33). Given that members of the genus Actinoplanes are the source of teicoplanin and acarbose, it will be exciting to find out in future if the developmental processes regulated by BldD in Actinoplanes extend to the control of their secondary metabolism.…”