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Comparative and Functional Genomics
Volume 5 (2004), Issue 4, Pages 304-327
http://dx.doi.org/10.1002/cfg.411
Research article

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

1Department of Biology, University of York, Box 373, Heslington, York YO10 5YW, UK
2Department of Chemistry, UMIST, Faraday Building, Sackville St, PO Box 88, Manchester M60 1QD, UK

Received 24 November 2003; Revised 24 March 2004; Accepted 1 April 2004

Copyright © 2004 Hindawi Publishing Corporation. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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 novel targets for anti-infectives is therefore of great importance. All protein sequences from three pathogens (Staphylococcus aureus, Mycobacterium tuberculosis and Escherichia coli O157:H7 EDL993) were assessed via comparative genomics methods for their suitability as antibacterial targets according to a number of criteria, including the essentiality of the protein, its level of sequence conservation, and its distribution in pathogens, bacteria and eukaryotes (especially humans). Each protein was scored and ranked based on weighted variants of these criteria in order to prioritize proteins as potential novel broad-spectrum targets for antibacterial drugs. A number of proteins proved to score highly in all three species and were robust to variations in the scoring system used. Sensitivity analysis indicated the quantitative contribution of each metric to the overall score. After further analysis of these targets, tRNA methyltransferase (trmD) and translation initiation factor IF-1 (infA) emerged as potential and novel antimicrobial targets very worthy of further investigation. The scoring strategy used might be of value in other areas of post-genomic drug discovery.