Biosynthesis of streptothricin and its related antibiotic BD-12

BD-12, which is produced by Streptomyces luteocolor NBRC 13826, is an analogue of the antibiotic streptothricins (STs). The first member of STs, ST-F, was isolated from Streptomyces lavendulae in 1943. ST-F consists of a carbamoylated D-gulosamine to which an L-β-lysine and the amide form of the unusual amino acid streptolidine (streptolidine lactam) are attached. To date, analogues with two to seven L-β-lysine oligopeptides [oligo(β-Lys)] have been identified in STs and STs carrying the longer oligo(β-Lys) side chains show greater antibiotic activities.

 In addition to STs, Streptomyces strains are known to produce other ST-related compounds: 12-carbamoyl STs, glycinothricin, citromycin, and BD-12. Some of these compounds have one or more N-methyl groups. Glycinothricin, citromycin, and BD-12 have a side chain of glycine or glycine analog instead of L-β-lysine.

 STs and ST-related compounds show antibiotic activity against both prokaryotes and eukaryotes. Therefore, none of them are currently used therapeutically because of their inherent toxicity. To date, many chemical modifications have been made to reduce the toxicities of STs against eukaryotes. However, very few successful examples have been reported. Therefore, the alteration of chemical structures of the ST family by engineering the biosynthetic pathway is great interest.

 We have reported that NRPSs catalyze the condensation reaction between carbamoylated D-gulosamine and L-β-lysine in ST biosynthesis. However, a different mechanism underlies the condensation reaction with glycine in BD-12 biosynthesis. Recent progress in the biosynthetic engineering of STs and ST-related compounds, and the consequent implications for their biosynthesis, are discussed.