Metabolic engineering of Bacillus subtilis based on genome-scale metabolic model to promote fengycin production

Fengycin is an important lipopeptide antibiotic that can be produced by Bacillus subtilis. However, the production capacity of the unmodified wild strain is very low. Therefore, a computationally guided engineering method was proposed to improve the fengycin production capacity. First, based on the annotated genome and biochemical information, a genome-scale metabolic model of Bacillus subtilis 168 was constructed. Subsequently, several potential genetic targets were identified through the flux balance analysis and minimization of metabolic adjustment algorithm that can ensure an increase in the production of fengycin. In addition, according to the results predicted by the model, the target genes accA (encoding acetyl-CoA carboxylase), cypC (encoding fatty acid beta-hydroxylating cytochrome P450) and gapA (encoding glyceraldehyde-3-phosphate dehydrogenase) were overexpressed in the parent strain Bacillus subtilis 168. The yield of fengycin was increased by 56.4, 46.6, and 20.5% by means of the overexpression of accA, cypC, and gapA, respectively, compared with the yield from the parent strain. The relationship between the model prediction and experimental results proves the effectiveness and rationality of this method for target recognition and improving fengycin production.