A Cryptic Polyene Biosynthetic Gene Cluster in Streptomyces calvus Is Expressed upon Complementation with a Functional bldA Gene

•Streptomyces calvus is a poor sporulator and exhibits a “bald” phenotype•Genome scanning revealed a point mutation in the bldA gene•Complementation with a correct bldA gene restored sporulation•Annimycin inhibits morphological differentiation in other Actinobacteria

SummaryStreptomyces calvus is best known as the producer of the fluorinated natural product nucleocidin. This strain of Streptomycetes is also unusual for displaying a “bald” phenotype that is deficient in the formation of aerial mycelium and spores. Genome sequencing of this organism revealed a point mutation in the bldA gene that is predicted to encode a misfolded Leu-tRNAUUA molecule. Complementation of S. calvus with a correct copy of bldA restored sporulation and additionally promoted production of a polyeneoic acid amide, 4-Z-annimycin, and a minor amount of the isomer, 4-E-annimycin. Bioassays reveal that these compounds inhibit morphological differentiation in other Actinobacteria. The annimycin gene cluster encoding a type 1 polyketide synthase was identified and verified through disruption studies. This study underscores the importance of the bldA gene in regulating the expression of cryptic biosynthetic genes.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (347 K)Download as PowerPoint slide