Aerobic Fermentation Strategy to Promote Nisin Production by Lactococcus lactis

Nisin, a natural, nontoxic antimicrobial peptide, has been widely studied for its broad-spectrum antibacterial activity against Gram-positive bacteria and its applications in food preservation and pharmaceuticals. However, the low nisin titer of Lactococcus lactis poses an obstacle to its large-scale industrial production. Here, we studied the metabolic basis of increased nisin production under aerobic conditions and proposed a high-efficiency fermentation strategy. Aerobic cultivation of L. lactis CF6 significantly increased intracellular ATP and the NAD⁺/NADH ratio, thus redirecting metabolic flux toward nisin production. Furthermore, cysteine availability and the supplementation of hemin and antioxidants effectively reduced oxidative stress caused by high dissolved oxygen, leading to a significant improvement in nisin titer. Through multimodule synergistic regulation and process optimization, a nisin titer of 18200 IU/mL was achieved in a 5 L bioreactor. In summary, this study lays the foundation for the metabolic engineering of L. lactis and provides valuable insights into the large-scale biomanufacturing of natural antimicrobial peptides.