Summary
The complete genome sequences of about 300 bacteria (mostly pathogenic) have been determined, and many more such projects are currently in progress. The detection of bacterial genes that are non-homologous to human genes and are essential for the survival of the pathogen represent a promising means of identifying novel drug targets. We present a subtractive genomics approach for the identification of putative drug targets in microbial genomes and demonstrate its execution using Pseudomonas aeruginosa as an example. The resultant analyses are in good agreement with the results of systematic gene deletion experiments. This strategy enables rapid potential drug target identification, thereby greatly facilitating the search for new antibiotics. It should be recognized that there are limitations to this computational approach for drug target identification. Distant gene relationships may be missed since the alignment scores are likely to have low statistical significance. In conclusion, the results of such a strategy underscore the utility of large genomic databases for in silico systematic drug target identification in the post-genomic era.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Miesel, L., Greene, J., and Black, T. A. (2003) Genetic strategies for antibacterial drug discovery. Nat. Rev. Genet. 4, 442–456.
Huynen, M. A., Diaz-Lazcoz, Y., and Bork, P. (1997) Differential genome display. Trends Genet. 13, 389–390.
Huynen, M., Dandekar, T., and Bork, P. (1998) Differential genome analysis applied to the species-specific features of Helicobacter pylori. FEBS Lett. 426, 1–5.
Sakharkar, K. R., Sakharkar, M. K., and Chow, V. T. (2004) A novel genomics approach for the identification of drug targets in pathogens, with special reference to Pseudomonas aeruginosa. In Silico Biol. 4, 355–360.
Bruccoleri, R. E., Dougherty, T. J., and Davison, D. B. (1998) Concordance analysis of microbial genomes. Nucleic Acids Res. 26, 4482–4486.
Sakharkar K. R., Sakharkar M. K., and Chow, V. T. (2006) Gene fusion in Helicobacter pylori: Making the ends meet. Antonie van Leeuwenhoek 89, 169–180.
Galperin, M. Y., and Koonin, E. V. (1999) Searching for drug targets in microbial genomes. Curr. Opin. Biotechnol. 10, 571–578.
Itaya, M. (1995) An estimation of minimal genome size required for life. FEBS Lett. 362, 257–260.
Tatusov R. L., Koonin E. V., Lipman D. J. (1997) A genomic perspective on protein families. Science 278 631–637
Koonin, E. V., Tatusov, R. L., and Galperin, M. Y. (1998) Beyond complete genomes: From sequence to structure and function. Curr. Opin. Struct. Biol. 8, 355–363.
Kobayashi, K., Ehrlich, S. D., Albertini, A., Amati, G., Andersen, K. K., Arnaud, M., et al. (2003) Essential Bacillus subtilis genes. Proc. Natl. Acad. Sci. USA 100, 4678–4683.
Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., et al. (2001) Initial sequencing and analysis of the human genome. Nature 409, 860–921.
Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J.,Sutton, G. G., et al. (2001) The sequence of the human genome. Science 291, 1304–1351.
Zhang, R., Ou, H. Y., and Zhang, C. T. (2004) DEG: A database of essential genes. Nucleic Acids Res. 32, D271–D272.
Wheeler, D. L., Church, D. M., Edgar, R., Federhen, S., Helmberg, W., Madden, T. L., et al. (2004) Database resources of the National Center for Biotechnology Information: Update. Nucleic Acids Res. 32, D35–D40.
Li, W., Jaroszewski, L., and Godzik, A. (2001) Clustering of highly homologous sequences to reduce the size of large protein databases. Bioinformatics 17, 282–283.
Stover, C. K., Pham, X. Q., Erwin, A. L., Mizoguchi, S. D., Warrener, P., Hickey, M. J., et al. (2000) Complete genome sequence of Pseudomonas aeruginosa PA01, an opportunistic pathogen. Nature 406, 959–964.
Payne, D. J., Warren, P. V., Holmes, D. J., Ji, Y., and Lonsdale, J. T. (2001) Bacterial fatty-acid biosynthesis: A genomics-driven target for antibacterial drug discovery. Drug Discov. Today 6, 537–544.
Heath, R. J., White, S. W., and Rock, C. O. (2002) Inhibitors of fatty acid synthesis as antimicrobial chemotherapeutics. Appl. Microbiol. Biotech. 58, 695–703.
Fraser, C. M., Gocayne, J. D., White, O., Adams, M. D., Clayton, R. A., Fleischmann, R. D., et al. (1995) The minimal gene complement of Mycoplasma genitalium. Science 270, 397–403.
Lewis, K. (1999) Multidrug resistance: Versatile drug sensors of bacterial cells. Curr. Biol. 9, R403–R407.
Clayton, R. A., White, O., Ketchum, K. A., and Venter, J. C. (1997) The first genome from the third domain of life. Nature 387, 459–462.
Smith, R. S., Wolfgang, M. C., and Lory, S. (2004). An adenylate cyclase-controlled signaling network regulates Pseudomonas aeruginosa virulence in a mouse model of acute pneumonia. Infect. Immun. 72, 1677–1684.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2008 Humana Press Inc.
About this protocol
Cite this protocol
Sakharkar, K.R., Sakharkar, M.K., Chow, V.T. (2008). Biocomputational Strategies for Microbial Drug Target Identification. In: Champney, W.S. (eds) New Antibiotic Targets. Methods In Molecular Medicine™, vol 142. Humana Press. https://doi.org/10.1007/978-1-59745-246-5_1
Download citation
DOI: https://doi.org/10.1007/978-1-59745-246-5_1
Publisher Name: Humana Press
Print ISBN: 978-1-58829-915-4
Online ISBN: 978-1-59745-246-5
eBook Packages: Springer Protocols