This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Gerdes, S. Y. Articles by Osterman, A. L. Search for Related Content PubMed PubMed Citation Articles by Gerdes, S. Y. Articles by Osterman, A. L.

From Genetic Footprinting to Antimicrobial Drug Targets: Examples in Cofactor Biosynthetic Pathways

Integrated Genomics Inc., Chicago, Illinois 60612

Received 17 January 2002/ Accepted 14 May 2002

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.

This article has been cited by other articles:

• Boshoff, H. I. M., Xu, X., Tahlan, K., Dowd, C. S., Pethe, K., Camacho, L. R., Park, T.-H., Yun, C.-S., Schnappinger, D., Ehrt, S., Williams, K. J., Barry, C. E. III (2008). Biosynthesis and Recycling of Nicotinamide Cofactors in Mycobacterium tuberculosis: AN ESSENTIAL ROLE FOR NAD IN NONREPLICATING BACILLI. J. Biol. Chem. 283: 19329-19341 [Abstract] [Full Text]  
• Sauve, A. A. (2008). NAD+ and Vitamin B3: From Metabolism to Therapies. J. Pharmacol. Exp. Ther. 324: 883-893 [Abstract] [Full Text]  
• Poncet-Montange, G., Assairi, L., Arold, S., Pochet, S., Labesse, G. (2007). NAD Kinases Use Substrate-assisted Catalysis for Specific Recognition of NAD. J. Biol. Chem. 282: 33925-33934 [Abstract] [Full Text]  
• Pollak, N., Niere, M., Ziegler, M. (2007). NAD Kinase Levels Control the NADPH Concentration in Human Cells. J. Biol. Chem. 282: 33562-33571 [Abstract] [Full Text]  
• Stockman, B. J., Lodovice, I. J., Fisher, D. A., Mccoll, A. S., Zhi Xie, (2007). A Nuclear Magnetic Resonance-Based Functional Assay for Nicotinamide Adenine Dinucleotide Synthetase. J Biomol Screen 12: 457-463 [Abstract]  
• Darley, P. I., Hellstern, J. A., Medina-Bellver, J. I., Marques, S., Schink, B., Philipp, B. (2007). Heterologous Expression and Identification of the Genes Involved in Anaerobic Degradation of 1,3-Dihydroxybenzene (Resorcinol) in Azoarcus anaerobius. J. Bacteriol. 189: 3824-3833 [Abstract] [Full Text]  
• Ciulli, A., Chirgadze, D. Y., Smith, A. G., Blundell, T. L., Abell, C. (2007). Crystal Structure of Escherichia coli Ketopantoate Reductase in a Ternary Complex with NADP+ and Pantoate Bound: SUBSTRATE RECOGNITION, CONFORMATIONAL CHANGE, AND COOPERATIVITY. J. Biol. Chem. 282: 8487-8497 [Abstract] [Full Text]  
• Gerlach, G., Reidl, J. (2006). NAD+ utilization in pasteurellaceae: simplification of a complex pathway.. J. Bacteriol. 188: 6719-6727 [Full Text]  
• Yang, K., Eyobo, Y., Brand, L. A., Martynowski, D., Tomchick, D., Strauss, E., Zhang, H. (2006). Crystal Structure of a Type III Pantothenate Kinase: Insight into the Mechanism of an Essential Coenzyme A Biosynthetic Enzyme Universally Distributed in Bacteria.. J. Bacteriol. 188: 5532-5540 [Abstract] [Full Text]  
• Zhang, Y.-M., White, S. W., Rock, C. O. (2006). Inhibiting Bacterial Fatty Acid Synthesis. J. Biol. Chem. 281: 17541-17544 [Abstract] [Full Text]  
• Gerdes, S. Y., Kurnasov, O. V., Shatalin, K., Polanuyer, B., Sloutsky, R., Vonstein, V., Overbeek, R., Osterman, A. L. (2006). Comparative Genomics of NAD Biosynthesis in Cyanobacteria.. J. Bacteriol. 188: 3012-3023 [Abstract] [Full Text]  
• Overbeek, R., Begley, T., Butler, R. M., Choudhuri, J. V., Chuang, H.-Y., Cohoon, M., de Crecy-Lagard, V., Diaz, N., Disz, T., Edwards, R., Fonstein, M., Frank, E. D., Gerdes, S., Glass, E. M., Goesmann, A., Hanson, A., Iwata-Reuyl, D., Jensen, R., Jamshidi, N., Krause, L., Kubal, M., Larsen, N., Linke, B., McHardy, A. C., Meyer, F., Neuweger, H., Olsen, G., Olson, R., Osterman, A., Portnoy, V., Pusch, G. D., Rodionov, D. A., Ruckert, C., Steiner, J., Stevens, R., Thiele, I., Vassieva, O., Ye, Y., Zagnitko, O., Vonstein, V. (2005). The Subsystems Approach to Genome Annotation and its Use in the Project to Annotate 1000 Genomes. Nucleic Acids Res 33: 5691-5702 [Abstract] [Full Text]  
• Sakuraba, H., Tsuge, H., Yoneda, K., Katunuma, N., Ohshima, T. (2005). Crystal Structure of the NAD Biosynthetic Enzyme Quinolinate Synthase. J. Biol. Chem. 280: 26645-26648 [Abstract] [Full Text]  
• Merdanovic, M., Sauer, E., Reidl, J. (2005). Coupling of NAD+ Biosynthesis and Nicotinamide Ribosyl Transport: Characterization of NadR Ribonucleotide Kinase Mutants of Haemophilus influenzae. J. Bacteriol. 187: 4410-4420 [Abstract] [Full Text]  
• Leonardi, R., Chohnan, S., Zhang, Y.-M., Virga, K. G., Lee, R. E., Rock, C. O., Jackowski, S. (2005). A Pantothenate Kinase from Staphylococcus aureus Refractory to Feedback Regulation by Coenzyme A. J. Biol. Chem. 280: 3314-3322 [Abstract] [Full Text]  
• Zhang, Y.-M., Frank, M. W., Virga, K. G., Lee, R. E., Rock, C. O., Jackowski, S. (2004). Acyl Carrier Protein Is a Cellular Target for the Antibacterial Action of the Pantothenamide Class of Pantothenate Antimetabolites. J. Biol. Chem. 279: 50969-50975 [Abstract] [Full Text]  
• Garavaglia, S., Raffaelli, N., Finaurini, L., Magni, G., Rizzi, M. (2004). A Novel Fold Revealed by Mycobacterium tuberculosis NAD Kinase, a Key Allosteric Enzyme in NADP Biosynthesis. J. Biol. Chem. 279: 40980-40986 [Abstract] [Full Text]  
• Gil, R., Silva, F. J., Pereto, J., Moya, A. (2004). Determination of the Core of a Minimal Bacterial Gene Set. Microbiol. Mol. Biol. Rev. 68: 518-537 [Abstract] [Full Text]  
• Ivey, R. A., Zhang, Y.-M., Virga, K. G., Hevener, K., Lee, R. E., Rock, C. O., Jackowski, S., Park, H.-W. (2004). The Structure of the Pantothenate Kinase{middle dot}ADP{middle dot}Pantothenate Ternary Complex Reveals the Relationship between the Binding Sites for Substrate, Allosteric Regulator, and Antimetabolites. J. Biol. Chem. 279: 35622-35629 [Abstract] [Full Text]  
• Kang, Y., Durfee, T., Glasner, J. D., Qiu, Y., Frisch, D., Winterberg, K. M., Blattner, F. R. (2004). Systematic Mutagenesis of the Escherichia coli Genome. J. Bacteriol. 186: 4921-4930 [Abstract] [Full Text]  
• Genschel, U. (2004). Coenzyme A Biosynthesis: Reconstruction of the Pathway in Archaea and an Evolutionary Scenario Based on Comparative Genomics. Mol Biol Evol 21: 1242-1251 [Abstract] [Full Text]  
• Lewis, L. M., Engle, L. J., Pierceall, W. E., Hughes, D. E., Shaw, K. J. (2004). Affinity Capillary Electrophoresis for the Screening of Novel Antimicrobial Targets. J Biomol Screen 9: 303-308 [Abstract]  
• Fischer, H. P., Brunner, N. A., Wieland, B., Paquette, J., Macko, L., Ziegelbauer, K., Freiberg, C. (2004). Identification of Antibiotic Stress-Inducible Promoters: A Systematic Approach to Novel Pathway-Specific Reporter Assays for Antibacterial Drug Discovery. Genome Res. 14: 90-98 [Abstract] [Full Text]  
• Jacobs, M. A., Alwood, A., Thaipisuttikul, I., Spencer, D., Haugen, E., Ernst, S., Will, O., Kaul, R., Raymond, C., Levy, R., Chun-Rong, L., Guenthner, D., Bovee, D., Olson, M. V., Manoil, C. (2003). Comprehensive transposon mutant library of Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 100: 14339-14344 [Abstract] [Full Text]  
• Kupke, T., Hernandez-Acosta, P., Culianez-Macia, F. A. (2003). 4'-Phosphopantetheine and Coenzyme A Biosynthesis in Plants. J. Biol. Chem. 278: 38229-38237 [Abstract] [Full Text]  
• Gerdes, S. Y., Scholle, M. D., Campbell, J. W., Balazsi, G., Ravasz, E., Daugherty, M. D., Somera, A. L., Kyrpides, N. C., Anderson, I., Gelfand, M. S., Bhattacharya, A., Kapatral, V., D'Souza, M., Baev, M. V., Grechkin, Y., Mseeh, F., Fonstein, M. Y., Overbeek, R., Barabasi, A.-L., Oltvai, Z. N., Osterman, A. L. (2003). Experimental Determination and System Level Analysis of Essential Genes in Escherichia coli MG1655. J. Bacteriol. 185: 5673-5684 [Abstract] [Full Text]  
• Stancek, M., Isaksson, L. A., Ryden-Aulin, M. (2003). fusB is an allele of nadD, encoding nicotinate mononucleotide adenylyltransferase in Escherichia coli. Microbiology 149: 2427-2433 [Abstract] [Full Text]  
• Garavaglia, S., Galizzi, A., Rizzi, M. (2003). Allosteric Regulation of Bacillus subtilis NAD Kinase by Quinolinic Acid. J. Bacteriol. 185: 4844-4850 [Abstract] [Full Text]  
• Kobayashi, K., Ehrlich, S. D., Albertini, A., Amati, G., Andersen, K. K., Arnaud, M., Asai, K., Ashikaga, S., Aymerich, S., Bessieres, P., Boland, F., Brignell, S. C., Bron, S., Bunai, K., Chapuis, J., Christiansen, L. C., Danchin, A., Debarbouille, M., Dervyn, E., Deuerling, E., Devine, K., Devine, S. K., Dreesen, O., Errington, J., Fillinger, S., Foster, S. J., Fujita, Y., Galizzi, A., Gardan, R., Eschevins, C., Fukushima, T., Haga, K., Harwood, C. R., Hecker, M., Hosoya, D., Hullo, M. F., Kakeshita, H., Karamata, D., Kasahara, Y., Kawamura, F., Koga, K., Koski, P., Kuwana, R., Imamura, D., Ishimaru, M., Ishikawa, S., Ishio, I., Le Coq, D., Masson, A., Mauel, C., Meima, R., Mellado, R. P., Moir, A., Moriya, S., Nagakawa, E., Nanamiya, H., Nakai, S., Nygaard, P., Ogura, M., Ohanan, T., O'Reilly, M., O'Rourke, M., Pragai, Z., Pooley, H. M., Rapoport, G., Rawlins, J. P., Rivas, L. A., Rivolta, C., Sadaie, A., Sadaie, Y., Sarvas, M., Sato, T., Saxild, H. H., Scanlan, E., Schumann, W., Seegers, J. F. M. L., Sekiguchi, J., Sekowska, A., Seror, S. J., Simon, M., Stragier, P., Studer, R., Takamatsu, H., Tanaka, T., Takeuchi, M., Thomaides, H. B., Vagner, V., van Dijl, J. M., Watabe, K., Wipat, A., Yamamoto, H., Yamamoto, M., Yamamoto, Y., Yamane, K., Yata, K., Yoshida, K., Yoshikawa, H., Zuber, U., Ogasawara, N. (2003). Essential Bacillussubtilis genes. Proc. Natl. Acad. Sci. USA 100: 4678-4683 [Abstract] [Full Text]  
• Zhang, X., Kurnasov, O. V., Karthikeyan, S., Grishin, N. V., Osterman, A. L., Zhang, H. (2003). Structural Characterization of a Human Cytosolic NMN/NaMN Adenylyltransferase and Implication in Human NAD Biosynthesis. J. Biol. Chem. 278: 13503-13511 [Abstract] [Full Text]  
• Goryshin, I. Y., Naumann, T. A., Apodaca, J., Reznikoff, W. S. (2003). Chromosomal Deletion Formation System Based on Tn5 Double Transposition: Use For Making Minimal Genomes and Essential Gene Analysis. Genome Res. 13: 644-653 [Abstract] [Full Text]  
• Kurnasov, O. V., Polanuyer, B. M., Ananta, S., Sloutsky, R., Tam, A., Gerdes, S. Y., Osterman, A. L. (2002). Ribosylnicotinamide Kinase Domain of NadR Protein: Identification and Implications in NAD Biosynthesis. J. Bacteriol. 184: 6906-6917 [Abstract] [Full Text]  
• Zhou, J., Miller, J. H. (2002). Microbial Genomics--Challenges and Opportunities: The 9th International Conference on Microbial Genomes. J. Bacteriol. 184: 4327-4333 [Full Text]