Improved Fermentation Yield of Doramectin from Streptomyces avermitilis N72 by Strain Selection and Glucose Supplementation Strategies

Doramectin is a macrolide antiparasitic that is widely used in the treatment of mammalian parasitic diseases. Doramectin is usually produced by Streptomyces avermitilis fermentation using cyclohexanecarboxylic acid (CHC) as a precursor; however, the growth of S. avermitilis is usually inhibited by CHC, resulting in a low fermentation yield of doramectin. In this study, a high-yielding strain XY-62 was obtained using the S. avermitilis mutant strain S. avermitilis N72 as the starting strain, then combined with a CHC tolerance screening strategy using ultraviolet and nitrosoguanidine mutagenesis, and a 96 microtiter plate solid-state fermentation primary sieving and shake flask fermentation rescreening method. Compared with S. avermitilis N72, the doramectin fermentation yield increased by more than 1.3 times, and it was more adaptable to temperature, pH, and CHC concentration of the culture; additionally, the viability of the mycelial growth was enhanced. In addition, further studies on the high-yielding strain XY-62 revealed that the accumulation of doramectin could be further increased by glucose supplementation during the fermentation process, and the yield of doramectin reached 1068 mu g/mL by scaling up the culture in 50 L fermenters; this has the potential for industrial production. Therefore, mutagenesis combined with CHC tolerance screening is an effective way to enhance the fermentation production of doramectin by S. avermitilis. Our strategy and findings can help to improve the production of doramectin in industrial strains of S. avermitilis.

Automated summary

By mutagenesis and CHC tolerance screening, a high-yielding strain XY-62 was obtained, which showed a 1.3-fold increase in doramectin fermentation yield compared to S. avermitilis N72. The strain was more adaptable to temperature, pH, and CHC concentration, and exhibited enhanced mycelial growth viability. Further studies revealed that glucose supplementation during the fermentation process could further increase doramectin accumulation, with a yield of 1068 μg/mL achieved in scaled-up cultures. This highlights the potential for industrial production of doramectin using S. avermitilis.