Abstract
SummaryIn a 54 m3 large‐scale penicillin fermentor, the cells experience substrate gradient cycles at the timescales of global mixing time about 20–40 s. Here, we used an intermittent feeding regime (IFR) and a two‐compartment reactor (TCR) to mimic these substrate gradients at laboratory‐scale continuous cultures. The IFR was applied to simulate substrate dynamics experienced by the cells at full scale at timescales of tens of seconds to minutes (30 s, 3 min and 6 min), while the TCR was designed to simulate substrate gradients at an applied mean residence time (τc) of 6 min. A biological systems analysis of the response of an industrial high‐yielding P. chrysogenum strain has been performed in these continuous cultures. Compared to an undisturbed continuous feeding regime in a single reactor, the penicillin productivity (qPenG) was reduced in all scale‐down simulators. The dynamic metabolomics data indicated that in the IFRs, the cells accumulated high levels of the central metabolites during the feast phase to actively cope with external substrate deprivation during the famine phase. In contrast, in the TCR system, the storage pool (e.g. mannitol and arabitol) constituted a large contribution of carbon supply in the non‐feed compartment. Further, transcript analysis revealed that all scale‐down simulators gave different expression levels of the glucose/hexose transporter genes and the penicillin gene clusters. The results showed that qPenG did not correlate well with exposure to the substrate regimes (excess, limitation and starvation), but there was a clear inverse relation between qPenG and the intracellular glucose level.
Highlights
In industrial practice, microbial fermentations are often operated as substrate-limited, fed-batch cultivations with high cell densities to obtain high volumetric productivities at low operational costs (Yamane and Shimizu, 1984)
As discussed elsewhere (Haringa et al, 2016), there are no indications that significant oxygen limitation has occurred in the 54 m3 industrial penicillin fermentation case and we only focused on the substrate gradients under the simulated industrial conditions
To investigate the effect of dynamic substrate gradients, occurring in the 54 m3 industrial -scale penicillin fermentor (Haringa et al, 2016), on the metabolism and penicillin production of a high-yielding P. chrysogenum strain, the strain was cultivated in the glucose-limited chemostat set-ups as intermittent feeding regime (IFR) and twocompartment reactor (TCR) scale-down simulators (Fig. 1)
Summary
In a 54 m3 large-scale penicillin fermentor, the cells experience substrate gradient cycles at the timescales of global mixing time about 20–40 s. We used an intermittent feeding regime (IFR) and a twocompartment reactor (TCR) to mimic these substrate gradients at laboratory-scale continuous cultures. The IFR was applied to simulate substrate dynamics experienced by the cells at full scale at timescales of tens of seconds to minutes (30 s, 3 min and 6 min), while the TCR was designed to simulate substrate gradients at an applied mean residence time (sc) of 6 min. A biological systems analysis of the response of an industrial high-yielding P. chrysogenum strain
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