title: Model-driven discovery of synergistic inhibitors against E. coli and S. enterica serovar Typhimurium targeting a novel synthetic lethal pair, aldA and prpC.
abstract: Mathematical models of biochemical networks form a cornerstone of bacterial systems biology. Inconsistencies between simulation output and experimental data point to gaps in knowledge about the fundamental biology of the organism. One such inconsistency centers on the gene aldA in Escherichia coli: it is essential in a computational model of E. coli metabolism, but experimentally it is not. Here, we reconcile this disparity by providing evidence that aldA and prpC form a synthetic lethal pair, as the double knockout could only be created through complementation with a plasmid-borne copy of aldA. Moreover, virtual and biological screening against the two proteins led to a set of compounds that inhibited the growth of E. coli and Salmonella enterica serovar Typhimurium synergistically at 100-200 μM individual concentrations. These results highlight the power of metabolic models to drive basic biological discovery and their potential use to discover new combination antibiotics.
authors.affiliation: Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University Cairo, Egypt ; Department of Bioengineering, University of California, San Diego La Jolla, CA, USA.
authors.forename: Ramy K
authors.initials: RK
authors.lastname: Aziz
authors.affiliation: Department of Bioengineering, University of California, San Diego La Jolla, CA, USA.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Khaw
authors.affiliation: Department of Bioengineering, University of California, San Diego La Jolla, CA, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Monk
authors.affiliation: Department of Bioengineering, University of California, San Diego La Jolla, CA, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brunk
authors.affiliation: Computer-Aided Drug Discovery, Albany Molecular Research, Inc., Albany NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Lewis
authors.affiliation: Biology and Pharmacology, Albany Molecular Research Singapore Research Centre, Pte. Ltd., Singapore Singapore.
authors.forename: Suh I
authors.initials: SI
authors.lastname: Loh
authors.affiliation: Biology and Pharmacology, Albany Molecular Research Singapore Research Centre, Pte. Ltd., Singapore Singapore.
authors.forename: Arti
authors.initials: A
authors.lastname: Mishra
authors.affiliation: Biology and Pharmacology, Albany Molecular Research Singapore Research Centre, Pte. Ltd., Singapore Singapore.
authors.forename: Amrita A
authors.initials: AA
authors.lastname: Nagle
authors.affiliation: Biology and Pharmacology, Albany Molecular Research Singapore Research Centre, Pte. Ltd., Singapore Singapore.
authors.forename: Chitkala
authors.initials: C
authors.lastname: Satyanarayana
authors.affiliation: Biology and Pharmacology, Albany Molecular Research Singapore Research Centre, Pte. Ltd., Singapore Singapore.
authors.forename: Saravanakumar
authors.initials: S
authors.lastname: Dhakshinamoorthy
authors.affiliation: Computer-Aided Drug Discovery, Albany Molecular Research, Inc., Albany NY, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Luche
authors.affiliation: Computer-Aided Drug Discovery, Albany Molecular Research, Inc., Albany NY, USA.
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Kitchen
authors.affiliation: Department of Bioengineering, University of California, San Diego La Jolla, CA, USA.
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Andrews
authors.affiliation: Department of Bioengineering, University of California, San Diego La Jolla, CA, USA.
authors.forename: Bernhard Ø
authors.initials: BØ
authors.lastname: Palsson
authors.affiliation: Department of Bioengineering, University of California, San Diego La Jolla, CA, USA ; The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark Hørsholm, Denmark.
authors.forename: Pep
authors.initials: P
authors.lastname: Charusanti
keywords: antibiotic development; bacterial metabolism; drug discovery; metabolic reconstruction; model-based drug target discovery; pathway gap filling; synthetic lethality; systems biology