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Aerobic microbial cultivations are industrially important group of processes and pose challenges for the reactor design. In particular, estimation of industrial scale conditions is difficult from laboratory and pilot scale data. Due to complex interaction of gas/liquid phase hydrodynamics, mass transfer parameters and microbial metabolism, both improvement of modelling tools and reactor design are desired. We present an approach to estimate growth conditions in industrial scale reactor by combining black-box metabolic models with CFD-model.
The reactor type used here is Outotec OKTOP9000®, which is used in the industrial hydrometallurgical processes at 900 m3 scale. It is adopted to a laboratory setting and compared to stirred tank reactor (STR) in gas dispersion, mass transfer and yeast cultivation experiments. In addition, a kinetic model for the yeast growth is developed based on literature sources and validated by the laboratory scale batch cultivations. This kinetic model is used along with CFD-model that is developed to describe the flow and mass transfer conditions in the industrial scale reactor.
The laboratory scale experiments show the feasibility of OKTOP9000® reactor when compared to STR, particularly with improved gas handling capacity. The modelling approach shows qualitatively similar behavior in the large scale simulations when compared to laboratory scale cultivations.
Multidrug resistance (MDR) in tumors and pathogens remains a major problem in the efficacious treatment of patients by reduction of therapy options and subsequent treatment failure. Various mechanisms are described to be involved in the development of MDR with overexpression of ATP-binding cassette (ABC) transporters reflecting the most extensively studied. These membrane transporters translocate a wide variety of substrates utilizing energy from ATP hydrolysis leading to decreased intracellular drug accumulation and impaired drug efficacy. One treatment strategy might be inhibition of transporter-mediated efflux by small molecules. Isocoumarins and 3,4-dihydroisocoumarins are a large group of natural products derived from various sources with great structural and functional variety, but have so far not been in the focus as potential MDR reversing agents. Thus, three natural products and nine novel 3,4-dihydroisocoumarins were designed and analyzed regarding cytotoxicity induction and inhibition of human ABC transporters P-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) in a variety of human cancer cell lines as well as the yeast ABC transporter Pdr5 in Saccharomyces cerevisiae. Dual inhibitors of P-gp and BCRP and inhibitors of Pdr5 were identified, and distinct structure-activity relationships for transporter inhibition were revealed. The strongest inhibitor of P-gp and BCRP, which inhibited the transporters up to 80 to 90% compared to the respective positive controls, demonstrated the ability to reverse chemotherapy resistance in resistant cancer cell lines up to 5.6-fold. In the case of Pdr5, inhibitors were identified that prevented substrate transport and/or ATPase activity with IC50 values in the low micromolar range. However, cell toxicity was not observed. Molecular docking of the test compounds to P-gp revealed that differences in inhibition capacity were based on different binding affinities to the transporter. Thus, these small molecules provide novel lead structures for further optimization.