P112: Heterologous biosynthesis of erythromycin A and its analogs in E. coli

Erythromycin A is a well-established natural product with a broad anti-bacterial spectrum. The compound possesses a complex architecture with a polyketide macrolactone ring, two sugar residues, and ten asymmetric centers.  The erythromycin native producer, Saccharopolyspora erythraea, generates erythromycin A from a ~60 kb gene cluster containing 3 large polyketide synthase genes and 17 additional genes responsible for sugar biosynthesis and attachment, macrolide modification, and erythromycin resistance.  We systematically transferred the gene cluster from S. erythraea to E. coli for reconstituted biosynthesis of erythromycin A with titers reaching 10 mg/L.  This was accomplished by the active and coordinated expression of 26 genes aided by manipulation of the native metabolism of E. coli. Furthermore, polyketide biosynthesis was then rationally designed and modified to produce two erythromycin analogs with novel molecular architecture. Success thus establishes E. coli as a viable option for the heterologous production of erythromycin A and erythromycin-derived unnatural compounds.