RRC ID 1628
Author Gerdes SY, Scholle MD, D'Souza M, Bernal A, Baev MV, Farrell M, Kurnasov OV, Daugherty MD, Mseeh F, Polanuyer BM, Campbell JW, Anantha S, Shatalin KY, Chowdhury SA, Fonstein MY, Osterman AL.
Title From genetic footprinting to antimicrobial drug targets: examples in cofactor biosynthetic pathways.
Journal J. Bacteriol.
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.
Volume 184(16)
Pages 4555-72
Published 2002-8
PMID 12142426
PMC PMC135229
MeSH Anti-Bacterial Agents Coenzyme A / biosynthesis* DNA Footprinting DNA Transposable Elements Drug Design Drug Resistance, Bacterial Escherichia coli / drug effects Escherichia coli / genetics Escherichia coli / metabolism* Flavin Mononucleotide / biosynthesis Flavin-Adenine Dinucleotide / biosynthesis* Genome, Bacterial Mutagenesis, Insertional NADP / biosynthesis* Nicotinamide-Nucleotide Adenylyltransferase / metabolism Phosphotransferases (Alcohol Group Acceptor) / genetics Substrate Specificity
IF 3.234
Times Cited 195