Bioinformatics and the discovery of novel anti-microbial targets.

ABSTRACT

Genomic research is playing a critical role in the discovery of new anti-microbial drugs. The rapid increase in bacterial and eukaryotic genome sequences allows for new and innovative ways for obtaining antimicrobial protein targets. Here, we describe a two level strategy for target identification and validation using computers (in silico). First, large scale comparative analyses of genome sequences were used to identify highly conserved genes which might be essential for in vitro and/or in vivo survival of bacterial pathogens. Lab-based experiments provided confirmation or validation of the hypothesis of in silico essentiality for over 350 individual genes. Over 200 validated, broad spectrum; yet highly specific gene targets, were identified in community infection pathogens. The second part of the target discovery strategy is an in-depth evolutionary, structural and cellular analysis of key drug targets. As an example, phylogenetic and structural analyses suggest that sequence and binding-pocket conservation in FabH (beta-ketoacyl-ACP synthase III) would allow for the development of small molecule inhibitors not only effective against a broad species spectrum of community bacterial pathogens but also as potential new therapies for tuberculosis and malaria.