title: Systems biology-guided identification of synthetic lethal gene pairs and its potential use to discover antibiotic combinations.
abstract: Mathematical models of metabolism from bacterial systems biology have proven their utility across multiple fields, for example metabolic engineering, growth phenotype simulation, and biological discovery. The usefulness of the models stems from their ability to compute a link between genotype and phenotype, but their ability to accurately simulate gene-gene interactions has not been investigated extensively. Here we assess how accurately a metabolic model for Escherichia coli computes one particular type of gene-gene interaction, synthetic lethality, and find that the accuracy rate is between 25% and 43%. The most common failure modes were incorrect computation of single gene essentiality and biological information that was missing from the model. Moreover, we performed virtual and biological screening against several synthetic lethal pairs to explore whether two-compound formulations could be found that inhibit the growth of Gram-negative bacteria. One set of molecules was identified that, depending on the concentrations, inhibits E. coli and S. enterica serovar Typhimurium in an additive or antagonistic manner. These findings pinpoint specific ways in which to improve the predictive ability of metabolic models, and highlight one potential application of systems biology to drug discovery and translational medicine.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt.|Department of Bioengineering, University of California, San Diego, La Jolla, California, 92093, USA.
authors.forename: Ramy K
authors.initials: RK
authors.lastname: Aziz
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, 92093, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Monk
authors.affiliation: Computer-Aided Drug Discovery, Albany Molecular Research, Inc., Albany, New York, 12203, USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Lewis
authors.affiliation: Albany Molecular Research Singapore Research Centre, Pte Ltd, Singapore, 117525.
authors.forename: Suh
authors.initials: S
authors.lastname: In Loh
authors.affiliation: Albany Molecular Research Singapore Research Centre, Pte Ltd, Singapore, 117525.
authors.forename: Arti
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Albany Molecular Research Singapore Research Centre, Pte Ltd, Singapore, 117525.
authors.forename: Amrita
authors.initials: A
authors.lastname: Abhay Nagle
authors.affiliation: Albany Molecular Research Singapore Research Centre, Pte Ltd, Singapore, 117525.
authors.forename: Chitkala
authors.initials: C
authors.lastname: Satyanarayana
authors.affiliation: Albany Molecular Research Singapore Research Centre, Pte Ltd, Singapore, 117525.
authors.forename: Saravanakumar
authors.initials: S
authors.lastname: Dhakshinamoorthy
authors.affiliation: Computer-Aided Drug Discovery, Albany Molecular Research, Inc., Albany, New York, 12203, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Luche
authors.affiliation: Computer-Aided Drug Discovery, Albany Molecular Research, Inc., Albany, New York, 12203, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kitchen
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, 92093, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Andrews
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, 92093, USA.
authors.forename: Nicole L
authors.initials: NL
authors.lastname: Fong
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, 92093, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Li
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, 92093, USA.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Palsson
authors.affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, 92093, USA.|The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2970 Hørsholm, Denmark.
authors.forename: Pep
authors.initials: P
authors.lastname: Charusanti
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D004338:Drug Combinations; D055808:Drug Discovery; D019453:Escherichia coli O157 / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D005517:Foodborne Diseases / Q000382:microbiology; D005804:Genes, Lethal / Q000235:genetics*; D007711:Klebsiella pneumoniae / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D008962:Models, Theoretical; D012486:Salmonella typhimurium / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*; D015010:Yersinia pestis / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004338:Drug Combinations