Identification of potential drug targets in Salmonella enterica sv. Typhimurium using metabolic modelling and experimental validation.
Salmonella enterica sv. 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 S. 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 the energy demand while growing in glucose minimal medium. By grouping reactions with similar flux responses, a subnetwork 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. Eleven such sets were found to be essential for the production of biomass precursors. Experimental investigation of seven of these showed that knockouts of the associated genes resulted in attenuated growth for four pairs of reactions, whilst three single reactions were shown to be essential for growth.
Department of Medical and Biological Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 OBP, UK.
Hassan B
HB
Hartman
Department of Medical and Biological Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 OBP, UK.
David A
DA
Fell
Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
Sergio
S
Rossell
Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
Peter Ruhdal
PR
Jensen
Department of Food and Nutritional Sciences, University of Reading, Reading, UK.
Martin J
MJ
Woodward
Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
Lotte
L
Thorndahl
Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
Lotte
L
Jelsbak
Department of Veterinary Disease Biology, University of Copenhagen, Copenhagen, Denmark.
John Elmerdahl
JE
Olsen
Department of Infectious Diseases, Mount Sinai School of Medicine, New York, NY, USA.
Anu
A
Raghunathan
Department of Infectious Diseases, Mount Sinai School of Medicine, New York, NY, USA.
Simon
S
Daefler
Department of Medical and Biological Sciences, Oxford Brookes University, Gipsy Lane, Headington, Oxford OX3 OBP, UK.
Mark G
MG
Poolman
D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018533:Biomass; D003198:Computer Simulation; D003470:Culture Media / Q000737:chemistry; D055786:Gene Knockout Techniques; D023281:Genomics; D005947:Glucose / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development
D000900:Anti-Bacterial Agents; D003470:Culture Media; D005947:Glucose