title: An antibiotic target ranking and prioritization pipeline combining sequence, structure and network-based approaches exemplified for Serratia marcescens.
abstract: We investigate a drug target screening pipeline comparing sequence, structure and network-based criteria for prioritization. Serratia marcescens, an opportunistic pathogen, serves as test case. We rank according to (i) availability of three dimensional structures and lead compounds, (ii) not occurring in man and general sequence conservation information, and (iii) network information on the importance of the protein (conserved protein-protein interactions; metabolism; reported to be an essential gene in other organisms). We identify 45 potential anti-microbial drug targets in S. marcescens with KdsA involved in LPS biosynthesis as top candidate drug target. LpxC and FlgB are further top-ranked targets identified by interactome analysis not suggested before for S. marcescens. Pipeline, targets and complementarity of the three approaches are evaluated by available experimental data and genetic evidence and against other antibiotic screening pipelines. This supports reliable drug target identification and prioritization for infectious agents (bacteria, parasites, fungi) by these bundled complementary criteria.
authors.affiliation: Department of Bioinformatics, Biocenter, Am Hubland, D-97074 Würzburg, Germany; Department of Microbiology, Biocenter, Am Hubland, D-97074 Würzburg, Germany. Electronic address: shishir.gupta@uni-wuerzburg.de.
authors.forename: Shishir K
authors.initials: SK
authors.lastname: Gupta
authors.affiliation: Department of Microbiology, Biocenter, Am Hubland, D-97074 Würzburg, Germany. Electronic address: roy@biozentrum.uni-wuerzburg.de.
authors.forename: Roy
authors.initials: R
authors.lastname: Gross
authors.affiliation: Department of Bioinformatics, Biocenter, Am Hubland, D-97074 Würzburg, Germany; EMBL Heidelberg, BioComputing Unit, Meyerhofstraße 1, 69117 Heidelberg, Germany. Electronic address: dandekar@biozentrum.uni-wuerzburg.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dandekar
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry*; D004352:Drug Resistance, Microbial / Q000187:drug effects; D006801:Humans; D060066:Protein Interaction Maps; D017386:Sequence Homology, Amino Acid; D012706:Serratia marcescens / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins
keywords: 3D structure; Anti-microbial resistance; Compound; Homology; Lead; Network analysis; Nosocomial infections; Pharmacological target; Protein-protein interaction