Identification of potential drug targets in Salmonella Typhimurium using metabolic modelling and experimental validation

Hartman, H. B., Fell, D. A., Rossell, S., Jensen, P. R., Woodward, M. J., Thorndahl, L., Jelsbak, L., Olsen, J. E., Raghunathan, A., Daefler, S. and Poolman, M. G. (2014) Identification of potential drug targets in Salmonella Typhimurium using metabolic modelling and experimental validation. Microbiology, 160 (6). pp. 1252-1266. ISSN 1350-0872 doi: 10.1099/mic.0.076091-0

Abstract/Summary

almonella enterica serovar Typhimurium is an established model organism for Gram-negative, intracellular pathogens. Owing to the rapid spread of resistance to antibiotics among this group of pathogens, new approaches to identify suitable target proteins are required. Based on the genome sequence of Salmonella Typhimurium and associated databases, a genome-scale metabolic model was constructed. Output was based on an experimental determination of the biomass of Salmonella when growing in glucose minimal medium. Linear programming was used to simulate variations in energy demand, while growing in glucose minimal medium. By grouping reactions with similar flux responses, a sub-network of 34 reactions responding to this variation was identified (the catabolic core). This network was used to identify sets of one and two reactions, that when removed from the genome-scale model interfered with energy and biomass generation. 11 such sets were found to be essential for the production of biomass precursors. Experimental investigation of 7 of these showed that knock-outs of the associated genes resulted in attenuated growth for 4 pairs of reactions, while 3 single reactions were shown to be essential for growth.