Bacterial genomics: potential for antimicrobial drug discovery.

Abstract

The sequencing of entire bacterial genomes is becoming increasingly routine, promising to revolutionise approaches to identifying putative antimicrobial drug targets. In silico methods can be used to identify putative gene products by comparing sequences of biochemically characterised enzymes and proteins with data produced by sequencing projects. Comparative genomics between a pathogenic bacterium versus nonpathogen as well as pathogen versus host can identify molecular targets that would be ideal for future investigation. The aim of these comparisons would be to identify genes that code for pathogenicity factors in the bacterium or genes essential for bacterial survival. The latter set of genes includes those that are nonfunctional or redundant in the host as well as genes absent from the host but essential in the pathogen. The products of these genes would be ideal targets for antimicrobial compounds. If compounds could be generated that disrupt the pathogen's ability to thrive but not affect the host, since there is a lack of the targeted protein, they could prove to be powerful therapeutics. An elegant example illustrating the power of comparative genomics involves comparison of the pathways of bacterial and eukaryotic aminoacyl-tRNA synthesis. Comparison of pathogenic bacterial genomes shows that many bacteria lack the genes encoding either one or two specific aminoacyl-tRNA synthetases, enzymes involved in ensuring correct aminoacylation of tRNA for subsequent translation of the genetic code. Bacteria have an alternative pathway by which amide aminoacyl-tRNAs are formed. Comparative genomics has demonstrated that this pathway is uniquely prokaryotic/archaeal and also relatively widely found in pathogenic bacteria, indicating the potential of the catalytic enzymes of the pathway as targets for novel antimicrobial drugs.