Fed-Batch Biomolecule Production by Bacillus subtilis: A State of the Art Review

Bacillus subtilis is a highly promising production system for various biomolecules. This review begins with the algorithm of fed-batch operations (FBOs) and then illustrates the approaches to design the initial production medium and/or feed stream. Additionally, the feeding strategies developed with or without feedback control for fed-batch B. subtilis fermentations were compiled with a special emphasis on recombinant protein (r-protein) production. For biomolecule production by wild-type B. subtilis, due to the different intracellular production patterns, no consensus exists on the FBO strategy that gives the maximum productivity, whereas for r-protein production appropriate feeding strategies vary depending on the promoter used. Thus, we conclude that the B. subtilis community is still seeking an approved strong promoter and generalized FBO strategies.

TrendsAs a promising production system, Bacillus subtilis has been widely used for extracellular production of both homologous and heterologous proteins. To increase the secretion level of heterologous proteins, the physical and chemical properties of the recombinant protein (r-protein) and consequently its harmony with the signal peptide used and the secretion pathway of B. subtilis should be analyzed.Since B. subtilis is mainly preferred for homologous enzyme production at industrial scale as any other Bacillus species, now the knowledge obtained from the enzyme industry should be transferred to pharmaceutical protein production.For fed-batch r-protein production, the promoter determines the most efficient feeding strategy to be used. Hence, it is time to develop generalized fed-batch operation strategies based on a strong promoter approved by the B. subtilis community.