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Background  Avermectin and milbemycin are important 16-membered macrolides that have been widely used as pesticides in agriculture. However, the wide use of these pesticides inevitably causes serious drug resistance, it is therefore imperative to develop new avermectin and milbemycin analogs. The biosynthetic gene clusters of avermectin and milbemycin have been identified and the biosynthetic pathways have been elucidated. Combinatorial biosynthesis by domain swap provides an efficient strategy to generate chemical diversity according to the module polyketide synthase (PKS) assembly line.    Results  The substitution of  ave DH2-KR2 located in avermectin biosynthetic gene cluster in the industrial avermectin-producing strain  Streptomyces avermitilis  NA-108 with the DNA regions  mil DH2-ER2-KR2 located in milbemycin biosynthetic gene cluster in  Streptomyces bingchenggensis  led to  S. avermitilis  AVE-T27, which produced ivermectin B1a with high yield of 3450 ± 65 μg/ml. The subsequent replacement of  ave LAT-ACP encoding the loading module of avermectin PKS with  mil LAT-ACP encoding the loading module of milbemycin PKS led to strain  S. avermitilis  AVE-H39, which produced two new avermectin derivatives 25-ethyl and 25-methyl ivermectin ( 1  and  2 ) with yields of 951 ± 46 and 2093 ± 61 μg/ml, respectively. Compared to commercial insecticide ivermectin, the mixture of 25-methyl and 25-ethyl ivermectin ( 2 : 1  = 3:7) exhibited 4.6-fold increase in insecticidal activity against  Caenorhabditis elegans . Moreover, the insecticidal activity of the mixture of 25-methyl and 25-ethyl ivermectin was 2.5-fold and 5.7-fold higher than that of milbemycin A3/A4 against  C. elegans  and the second-instar larva of  Mythimna separate , respectively.    Conclusions  Two new avermectin derivatives 25-methyl and 25-ethyl ivermectin were generated by the domain swap of avermectin PKS. The enhanced insecticidal activity of 25-methyl and 25-ethyl ivermectin implied the potential use as insecticide in agriculture. Furthermore, the high yield and genetic stability of the engineered strains  S. avermitilis  AVE-T27 and AVE-H39 suggested the enormous potential in industrial production of the commercial insecticide ivermectin and 25-methyl/25-ethyl ivermectins, respectively.    Electronic supplementary material  The online version of this article (doi:10.1186/s12934-015-0337-y) contains supplementary material, which is available to authorized users.

Designed biosynthesis of 25-methyl and 25-ethyl ivermectin with enhanced insecticidal activity by domain swap of avermectin polyketide synthase