(341b) A Systems-Biology Approach to Investigate the Antimicrobial Activity of Oleuropein

In recent years, there is a considerable interest regarding the use of natural antimicrobial agents as food additives to inhibit the growth of food pathogens. Oleuropein and its hydrolysis products, including 3,4-dihydroxy-phenylethanol (hydroxytyrosol), elenolic acid and aglycon [1], are olive phenolic compounds that have antimicrobial effects to a variety of bacteria and fungi such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Candida albicans [2-3]. The proposed antimicrobial mechanism of oleuropein is due to its surface activity at the bacterial cell membrane: molecular interactions between oleuropein and the phosphate group might modify the phospholipid/water interface properties [4]. In particular, oleuropein was proven to cause leakage of intracellular components such as potassium, phosphate and glutamate from bacteria along with the degradation of the cell membrane[5]. Additionally, oleuropein showed the ability to enhance nitric oxide production in macrophage cells, thus to fight against endotoxins and facilitate the elimination of pathogens[6]. From this, we hypothesize that intracellular metabolic reactions associated with nitric oxide should have larger fluxes for the antimicrobial function.

In this study, a genome-scale modeling approach which can help predict systems-level changes of intracellular metabolisms was adopted to investigate the effect of oleuropein on S. aureus, a common food-borne pathogen. Genome-scale modeling approaches, which incorporate genomic genes and metabolites in a metabolic reaction network, have been proved of excellent performance in predicting the systems-level changes of intracellular metabolisms in organisms under specific nutrient environment or treated by specific stimuli. Among all the pathogens that are inhibited by oleuropein, S. aureus has been widely studied experimentally [1], [7] as well as by modeling [8]â??[10]. In this work, the model developed by Becker et al.[8] was first extended to incorporate the nitric oxide reaction into the intracellular metabolism based on experimental research. The stress that oleuropein imposes on S. aureus was mimicked by regulating the export of potassium, phosphate and glutamate out of the cell. With decreased phosphate uptake rate and increased glutamate secretion rate, S. aureus growth fits experimental results [1] in the presence of oleuropein at various concentrations. In addition, the reactions and enzymes that are highly related to oleuropein stress are identified by flux balance analysis. This study provides the first genome-scale model for oleuropein metabolism study, and the results indicates that genome-scale modeling is a promising method for revealing the intracellular metabolisms of oleuropein biological properties and thus help to find the food and pharmaceutical applications of oleuropein.

 

References:

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