Comparative Genomic Assessment of Novel Broad-Spectrum Targets for Antibacterial Drugs

White, Thomas A.; Kell, Douglas B.

Comparative Genomic Assessment of Novel Broad-Spectrum Targets for Antibacterial Drugs

2004

White, Thomas A.(Department of Biology, University of York) | Kell, Douglas B.(Department of Chemistry, UMIST)

Single and multiple resistance to antibacterial drugs currently in use is spreading,since they act against only a very small number of molecular targets; finding noveltargets for anti-infectives is therefore of great importance. All protein sequences fromthree pathogens (Staphylococcus aureus, Mycobacterium tuberculosis and Escherichia coli O157:H7 EDL993) were assessed via comparative genomics methods for theirsuitability as antibacterial targets according to a number of criteria, including theessentiality of the protein, its level of sequence conservation, and its distribution inpathogens, bacteria and eukaryotes (especially humans). Each protein was scored andranked based on weighted variants of these criteria in order to prioritize proteins aspotential novel broad-spectrum targets for antibacterial drugs. A number of proteinsproved to score highly in all three species and were robust to variations in the scoringsystem used. Sensitivity analysis indicated the quantitative contribution of each metricto the overall score. After further analysis of these targets, tRNA methyltransferase(trmD) and translation initiation factor IF-1 (infA) emerged as potential and novelantimicrobial targets very worthy of further investigation. The scoring strategy usedmight be of value in other areas of post-genomic drug discovery.

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