1 Biocomputational Strategies for Microbial Drug Target Identification Kishore R. Sakharkar, Meena K. Sakharkar, and Vincent T. K. Chow Summary The complete genome sequences of about 300 bacteria (mostly pathogenic) have been deter- mined, and many more such projects are currently in progress. The detection of bacterial genes that are non-homologous to human genes and are essential for the survival of the pathogen represent a promising means of identifying novel drug targets. We present a subtractive genomics approach for the identification of putative drug targets in microbial genomes and demonstrate its execution using Pseudomonas aeruginosa as an example. The resultant analyses are in good agreement with the results of systematic gene deletion experiments. This strategy enables rapid potential drug target identification, thereby greatly facilitating the search for new antibiotics. It should be recognized that there are limitations to this computational approach for drug target identification. Distant gene relationships may be missed since the alignment scores are likely to have low statistical significance. In conclusion, the results of such a strategy underscore the utility of large genomic databases for in silico systematic drug target identification in the post-genomic era. Key Words: bacterial pathogens; comparative microbial genomics; essential genes; drug targets; antibiotics. 1. Introduction “Antibiotic” consists of the root words “anti,” meaning “opposed to” or “preventing,” and “biotic,” which is derived from the Greek word for life. In nature, various microbes and fungi secrete these compounds to gain an advantage in their microenvironment, and antibiotics are commonly isolated from such organisms. Between 1940 and 1960, the search for antibacterial agents relied From: Methods in Molecular Medicine, Vol. 142: New Antibiotic Targets Edited by: W. Scott Champney © Humana Press Inc., Totowa, NJ 1