Enhancing the production of amphotericin B by Strepyomyces nodosus in a 50-ton bioreactor based on comparative genomic analysis

Abstract

Amphotericin, as an important macrolide antibiotic, is synthesized by Streptomyces nodosus. A high-yield S. nodosus ZJB2016050 was obtained by mutagenesis in our lab with the advantages of high yield, short fermentation cycle and few by-products, which was more suitable for industrial production. The fermentation differences in 50-tons bioreactor between S. nodosus ATCC14899 and S. nodosus ZJB2016050 were compared. The amphotericin B (AmB) yield of S. nodosus ZJB2016050 was 9.73 mg/g at 96 h, which was 30% higher than that of S. nodosus ATCC14899. The by-product amphotericin A (AmA) production of S. nodosus ZJB2016050 was 78% lower than that of S. nodosus ATCC14899. By performing whole-genome sequencing of S. nodosus ZJB2016050 and comparative genome analysis with the wild-type S. nodosus ATCC14899, it was found that the two strains have high synteny, but each has a special gene fragment. The genes functions of fragment were identified in the amino acid transport and metabolism, carbohydrate metabolism and lipid transport and metabolism. The gene functions of SNP (single nucleotide polymorphism) genes were identified in amino acid transport and metabolism, carbohydrate metabolism, coenzyme metabolism and secondary metabolites biosynthesis. The difference in signal-regulation and transcription may be the main reason for the differences between these two strains. Three GntR family egulatory factors of S. nodosus ATCC14899 may reduce the synthesis of amphotericin. Based on the analysis of comparative genomes, the effects of corn oil in S. nodosus ATCC14899 and S. nodosus ZJB2016050 were also compared. The results showed that corn oil can promote the fermentation of S. nodosus ZJB2016050. The S. nodosus ZJB2016050 may degrade fatty acids faster, and the degraded acyl-coenzyme can be used to synthesize amphotericin.