Development of cultivation strategies for friulimicin production in Actinoplanes friuliensis

• A chemically defined medium for characterization of friulimicin biosynthesis.
• Phosphate and ammonium inhibited friulimicin biosynthesis.
• Perfusion processes enhanced volumetric productivity compared to fed-batch processes.
• Flux analyses revealed high energetic efficiency of growth.
• A large portion of the supplied amino acids is used as supplemental carbon source.

Actinoplanes friuliensis is a rare actinomycete which produces the highly potent lipopeptide antibiotic friulimicin. This lipopeptide antibiotic is active against a broad range of multi-resistant gram-positive bacteria such as methicillin-resistant Enterococcus sp. and Staphylococcus aureus (MRE, MRSA) strains.Antibiotic biosynthesis and regulation in actinomycetes is very complex. In order to study the biosynthesis of these species and to develop efficient production processes, standardized cultivation conditions are a prerequisite. For this reason a chemically defined production medium for A. friuliensis was developed. With this chemically defined medium it was possible to analyze the influence of medium components on growth and antibiotic biosynthesis.These findings were used to develop process strategies for friulimicin production. The focus of the project presented here was to develop cultivation strategies which included fed-batch and continuous cultivation processes. In fed-batch processes, volumetric productivities for friulimicin of 1–2 mg/l h were achieved. In a perfusion process, a very simple cell retention system, which works via sedimentation of the mycelial cell pellets, was used. With this system, stable continuous cultivations with cell retention were dependent on the dilution rate. With a dilution rate of 0.05 h−1, cell retention worked well and volumetric productivity of friulimicin was enhanced to 3–5 mg/l h. With a higher dilution rate of 0.1 h−1, friulimicin production ceased because cell retention was not possible any longer with this simple cell retention system. In order to support process development, cultivation data were used to characterize metabolic fluxes in the developed friulimicin production processes.