Reverse engineering enhanced avermectin production in an industrial strain

With a long history of microbial fermentation, China becomes a great fermentation country, but not powerful enough. The current model of development is still based on cheap labor and raw materials, consuming large amounts of energy and food, as well as the deterioration of the environment. Pharmaceutical industries clearly need to improve the efficiencies of existing fermentation processes and strain productivity to promote revenue growth. Long-term incremental mutagenesis has been the hallmark of conventional strain improvement process. How to solve the problem fundamentally is the key to promote the transition of China to a " powerful country in fermentation field".
Avermectin and its analogues exhibit an excellent anthelmintic activity against a variety of nematode and arthropod parasites. With few side effects against the host organism, they are widely used in the field of animal health, agriculture, and human infections. Recently, Dr. ZHANG Lixin’s group at Institute of Microbiology, Chinese Academy of Sciences adopted a proprietary approach to successfully improve the avermectins production in an industrial overproducer. By monitoring the transcriptional level of wild-type strain and industrial overproducer in production cultures via microarray analysis, they found the key gene σhrdB was relative to avermectin production. Manipulating on the key gene can coordinate the primary and secondary metabolism of cells and effectively improve the yield of avermectin B1a (with 52% production improvement), providing a route to optimize production in these complex regulatory systems. The engineered strain A56 was cultivated in a 180-m3 fermentor, in which the production of A56 has reached to 6382 μg/ml. It will bring a huge economic and social benefit to the enterprises. This study has been published in the journal Proceedings of the National Academy of Sciences on the 7th of June, 2010. The results indicated that manipulating the key genes revealed by reverse engineering can effectively improve the yield of the target metabolites, providing a route to optimize production in these complex regulatory systems.
This work was supported in part by grants from National 863 Project and the knowledge innovation project of the Chinese Academy of Sciences. Dr. ZHANG Lixin’s group took avermectin as an example to successfully expand the platform to other commercial significant microbial products.