Influence of load-induced morphological changes on the productivity of the filamentous pellet system Actinomadura namibiensis

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Filamentous microorganisms are central to many industrial biotechnological processes for the production of pharmaceutical compounds, antibiotics, proteins and organic acids. These microorganisms are commonly cultivated in stirred tanks or shaking flasks either as dispersed mycelia or pellets. A characteristic property of pelleted microorganisms is the tight connection between the pellet morphology and the pellet growth and productivity. In particular, the distribution of filaments within a pellet controls the internal mass transport which, in turn, affects the viability of filaments in the pellet core and determines potentional substrate limitations. While the morphology is vital for the viability and productivity of the pellets, past experimental investigations have shown that the morphology is predominantly shaped by the cultivation conditions and the mechanical loads experienced by the pellets. The strong interactions between mechanical loads, morphology and productivity on the level of a single pellet constitute the core of our research project. Based on kinetic expressions for the mechanical forces exerted on a pellet, the rate of change of morphology and the pellet metabolism, our objective is to conceptualise and develop a physical model of unprecedented fidelity for the analysis and prediction of the product yield in pelleted, submerged cultures. Perspectively, the novel model may be deployed to infer guidelines on reactor design, agitation and operation, targeting an optimum of power consumption, cultivation duration and product yield. This is in sharp contrast to existing models which are restricted to particular reactor configurations and operating conditions and in which load-induced morphological changes of the dispersed pellets are neglected. Within the scope of the proposed model, we combine a long-time description of pellet populations in a perfectly stirred reactor with the flow-resolved determination of pellet-specific load collectives on very short time scales, thus bridging the wide range of scales between characteristic mixing and cultivation times. The procaryot Actinomadura namibiensis serves as filamentous model organism as it is amenable to lab-scale cultivation in shaking flasks and produces the peptid antibiotic Labyrinthopeptin A1. In order to calibrate and validate the proposed model, we plan a two-track experimental campaign. On the one hand, the temporal changes of the substrate and product concentrations in the shaking flask are recorded along with the morphology distribution across the pellet population. On the other hand, pellet-specific experiments for the analysis of permeability, internal oxygen distribution and mechanical stiffness are undertaken.