Streptomyces avermitilis industrial strain as cell factory for Ivermectin B1a production

Ivermectin, a kind of valuable derivatives of Avermectin, is distinct from Avermectin due to the saturated bond at C22C23 position. Combinatorial biosynthesis of Ivermectins based on Avermectins biosynthetic gene cluster (ave) has been achieved recently, while the establishment of an Ivermectin homogeneous component producing strain is challenging because of the limited compatibility between the native and heterologous polyketide synthase (PKS) domains. In this study, the PKS module 2 Dehydratase (DH)-Enoylreductase (ER)-Ketoreductase (KR) domain set of Meilingmycin, which is another naturally occurring homologue of Avermectin, was employed to substitute the DH-KR domains of Avermectins PKS module 2 to generate an Ivermectin biosynthetic gene cluster (ive). Ivermectins B1a and A1a were heterologously biosynthesized in a classic actinomyces host Streptomyces lividans. The Avermectin B1a high-producing strain S. avermitilis 3-115 was genetically engineered to give an artificial host cell and Ivermectin B1a single component was effectively produced with a production of 1.25 ± 0.14 g/L. Keywords: Avermectin, Ivermectin, Meilingmycin, Domain swapping, Heterologo-us biosynthesi