Novel antibacterials: a genomics approach to drug discovery.
The appearance of antibiotic resistant pathogens, including vancomycin resistant Staphylococcus aureus, in the clinic has necessitated the development of new antibiotics. The golden age of antibiotic discovery, in which potent selective compounds were readily extracted from natural product extracts is over and novel approaches need to be implemented to cover the therapeutic shortfall. The generation of huge quantities of bacterial sequence data has allowed the identification of all the possible targets for therapeutic intervention and allowed the development of screens to identify inhibitors. Here, we described a number of target classes in which genomics has contributed to its identification. As a result of analyzing sequence data, all of the tRNA synthetases and all of the two-component signal transduction systems were readily isolated; which would not have been easily identified if whole genome sequences were not available. Fatty acid biosynthesis is a known antibacterial target, but genomics showed which genes in that pathway had the appropriate spectrum to be considered as therapeutic targets. Genes of unknown function may seem untractable targets, but if those that are broad spectrum and essential are identified, it becomes valuable to invest time and effort to determine their cellular role. In addition, we discuss the role of genomics in developing technologies that assist in the discovery of new antibiotics including microarray gridding technology. Genomics can also increase the chemical diversity against which the novel targets can be screened.
Chan
Pan F
PF
Department of Microbiology. Microbial, Musculoskeletal and Proliferative Diseases CEDD, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426-0989, USA.
Macarron
Ricardo
R
Payne
David J
DJ
Zalacain
Magdalena
M
Holmes
David J
DJ
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D016680:Genome, Bacterial; D023281:Genomics / Q000639:trends; D006801:Humans
D000900:Anti-Bacterial Agents