title: From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways.
abstract: Novel drug targets are required in order to design new defenses against antibiotic-resistant pathogens. Comparative genomics provides new opportunities for finding optimal targets among previously unexplored cellular functions, based on an understanding of related biological processes in bacterial pathogens and their hosts. We describe an integrated approach to identification and prioritization of broad-spectrum drug targets. Our strategy is based on genetic footprinting in Escherichia coli followed by metabolic context analysis of essential gene orthologs in various species. Genes required for viability of E. coli in rich medium were identified on a whole-genome scale using the genetic footprinting technique. Potential target pathways were deduced from these data and compared with a panel of representative bacterial pathogens by using metabolic reconstructions from genomic data. Conserved and indispensable functions revealed by this analysis potentially represent broad-spectrum antibacterial targets. Further target prioritization involves comparison of the corresponding pathways and individual functions between pathogens and the human host. The most promising targets are validated by direct knockouts in model pathogens. The efficacy of this approach is illustrated using examples from metabolism of adenylate cofactors NAD(P), coenzyme A, and flavin adenine dinucleotide. Several drug targets within these pathways, including three distantly related adenylyltransferases (orthologs of the E. coli genes nadD, coaD, and ribF), are discussed in detail.
authors.affiliation: Integrated Genomics Inc., Chicago, Illinois 60612, USA.
authors.forename: Svetlana Y
authors.initials: SY
authors.lastname: Gerdes
authors.forename: Michael D
authors.initials: MD
authors.lastname: Scholle
authors.forename: Mark
authors.initials: M
authors.lastname: D'Souza
authors.forename: Axel
authors.initials: A
authors.lastname: Bernal
authors.forename: Mark V
authors.initials: MV
authors.lastname: Baev
authors.forename: Michael
authors.initials: M
authors.lastname: Farrell
authors.forename: Oleg V
authors.initials: OV
authors.lastname: Kurnasov
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Daugherty
authors.forename: Faika
authors.initials: F
authors.lastname: Mseeh
authors.forename: Boris M
authors.initials: BM
authors.lastname: Polanuyer
authors.forename: John W
authors.initials: JW
authors.lastname: Campbell
authors.forename: Shubha
authors.initials: S
authors.lastname: Anantha
authors.forename: Konstantin Y
authors.initials: KY
authors.lastname: Shatalin
authors.forename: Shamim A K
authors.initials: SA
authors.lastname: Chowdhury
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Fonstein
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Osterman
mesh_terms: D000900:Anti-Bacterial Agents; D003065:Coenzyme A / Q000096:biosynthesis*; D018983:DNA Footprinting; D004251:DNA Transposable Elements; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D005486:Flavin Mononucleotide / Q000096:biosynthesis; D005182:Flavin-Adenine Dinucleotide / Q000096:biosynthesis*; D016680:Genome, Bacterial; D016254:Mutagenesis, Insertional; D009249:NADP / Q000096:biosynthesis*; D009612:Nicotinamide-Nucleotide Adenylyltransferase / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics; D013379:Substrate Specificity
chemical_list: D000900:Anti-Bacterial Agents; D004251:DNA Transposable Elements; D005182:Flavin-Adenine Dinucleotide; D009249:NADP; D005486:Flavin Mononucleotide; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D009612:Nicotinamide-Nucleotide Adenylyltransferase; D003065:Coenzyme A