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.
Highlights
Within two decades of the introduction of penicillin, the majority of the existing classes of antibacterial drugs had been discovered by systematic screening of natural product libraries
Data were collected from three pathogenic bacterial species, Staphylococcus aureus, Escherichia coli O157:H7 EDL993 and Mycobacterium tuberculosis
The entire set of sequences of proteins encoded by S. aureus, E. coli O157:H7 EDL993 and M. tuberculosis were downloaded from the NCBI website
Summary
Within two decades of the introduction of penicillin, the majority of the existing classes of antibacterial drugs had been discovered by systematic screening of natural product libraries. No new chemical classes of active antibacterial drugs were successfully introduced for a further 30 years (Hancock and Knowles, 1998). Microorganisms have shown themselves to be extremely versatile in overcoming the effects of antibacterial drugs. Antibacterial resistance has developed steadily as new agents have been introduced, and the past 10–15 years have shown a dramatic increase in the occurrence of resistant populations of microbes in both community and hospital environments (Struelens, 1998)
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