Substrate uptake, phosphorus repression, and effect of seed culture on glycopeptide antibiotic production: Process model development and experimental validation

Abstract

Actinomycetes, the soil borne bacteria which exhibit filamentous growth, are known for their ability to produce a variety of secondary metabolites including antibiotics. Industrial scale production of such antibiotics is typically carried out in a multi-substrate medium where the product formation may experience catabolite repression by one or more of the substrates. Availability of reliable process models is a key bottleneck in optimization of such processes. Here we present a structured kinetic model to describe the growth, substrate uptake and product formation for the glycopeptide antibiotic producer strain Amycolatopsis balhimycina DSM5908. The model is based on the premise that the organism is an optimal strategist and that the various metabolic pathways are regulated via key rate limiting enzymes. Further, the model accounts for substrate inhibition and catabolite repression. The model is also able to predict key phenomena such as simultaneous uptake of glucose and glycerol but with different specific uptake rates, and inhibition of glycopeptide production by high intracellular phosphate levels. The model is successfully applied to both production and seed medium with varying compositions and hence has good predictive ability over a variety of operating conditions. The model parameters are estimated via a well-designed experimental plan. Adequacy of the proposed model was established via checking the model sensitivity to its parameters and confidence interval calculations. The model may have applications in optimizing seed transfer, medium composition, and feeding strategy for maximizing production.