Application of Omics Technologies for in Silico Modelling to Understand Stress-Triggered Physiology of Escherichia coli and to Develop Novel Therapeutics
Zuyi Huang, Qian Jia and Thomas K. Wood
from: Pathogenic Escherichia coli: Evolution, Omics, Detection and Control (Edited by: Pina M. Fratamico, Yanhong Liu and Christopher H. Sommers). Caister Academic Press, U.K. (2018) Pages: 229-248.
Foodborne pathogens survive under oxidative stress conditions by changing their physiology and forming persister cells; persister cells are dormant cells that can awaken to cause chronic infections. While extensive experimental research has been conducted to investigate the genes and metabolic pathways associated with persister cell formation, no systems-level modelling approach has been developed to integrate these genes and other intracellular components to accelerate the identification of novel therapeutic targets for eliminating persister pathogens. In this work, we present the first genome-scale metabolic modelling approach to evaluate the ability of Escherichia coli to form persister cells under oxidative conditions and then identify gene targets that may be implemented to suppress persister cell formation. In particular, genomics data was integrated with a genome-scale metabolic model of E. coli to identify the reactions associated with persister cell formation. The change of activity levels of these reactions was then compared with the change of expression levels of genes obtained in persister cells to quantify the ability of the pathogen to form persister cells. Since rpoS-controlled genes and reactions have been reported for their important role in regulating persister cell formation, these genes were knocked out in the developed in-silico platform to evaluate the capability of these mutants to form persister cells. The results showed that the fluxes of rpoS-controlled reactions increase under oxidative stress and that the rpoS-deletion mutant showed an increased persister cell formation. In addition, 52 single-mutants were found to have reduced ability to form persister cells, and these genes are mainly involved in cell membrane ion transport and in energy and carbon and lipid metabolism. They can be used as therapeutic targets for eliminating persister pathogens. Finally, the challenges and limitations of genome-scale modelling are also discussed read more ...