The impact of genomics on novel antibacterial targets.
Antibiotic discovery has remained primarily focused on improving versions of existing classes of antibiotics which work on a limited set of bacterial targets. In addition, the characterization of these targets has focused almost entirely on Escherichia coli homologs. The advancing problems associated with resistant pathogens has driven a critical need for the discovery of new classes of antibiotics which will target novel bacterial functions required for viability and pathogenicity. Recent advances in DNA sequencing technology have now made it possible to elucidate the entire genomes of pathogenic bacteria. Comparative analysis of these genome sequences, driven by advancements in the availability of bioinformatic tools, is dramatically increasing our ability to interrogate the spectrum and selectivity of novel antibacterial target areas. In this review, we present an update on the antibiotic target areas of tRNA synthetases, two-component signal transduction systems, peptidoglycan biosynthesis, fatty acid biosynthesis and chorismate biosynthesis. We illustrate how the availability of genomes from a range of clinically important pathogens has enabled valid considerations of the limitations and advantages of particular targets based on their predicted spectrum and selectivity. Furthermore, we demonstrate how genomics is facilitating the characterization of targets from relevant pathogens and how these data, coupled with genomic-based technologies, provide new approaches for drug discovery.
Payne
D J
DJ
Anti-infectives Research (UP1345), SmithKline Beecham Pharmaceuticals, Collegeville, PA 19426-0989, USA. David_J_Payne@sbphrd.com
Wallis
N G
NG
Gentry
D R
DR
Rosenberg
M
M