Novel antimicrobial targets from combined pathogen and host genetics

The identification of drug targets for a given human disease, whether it is mainly environmental or genetic in origin, rests on an understanding of the molecular chain of events that unfold in the disease process. Anatomic pathology, biochemistry, cellular physiology, and pharmacology constitute the main traditional approaches towards identifying potential therapeutic targets. Genetic approaches, by determining the phenotypic consequences of mutations in genes and ordering these genes into functional pathways, are uniquely powerful in identifying novel gene products involved in a disease process. By characterizing mutations that block or reverse the disease phenotype, genetics can provide a direct route to target identification. The wild-type versions of these “suppressor” gene products are potential therapeutic targets, because chemical compounds that phenocopy suppressor gene mutations should similarly block the disease phenotype and thus constitute candidate therapeutic drug leads (1). Such genetic approaches to target identification are most feasible in well-studied model organisms with short generation times that are easily maintained in the laboratory, principally the yeast Saccharomyces cerevisiae, the soil nematode Caenorhabditis elegans, and the fruit fly Drosophila melanogaster. Using model organisms to study homologues of genes causally mutated in human disease is relatively well established. This approach has not often been applied to human infectious diseases, however, as most human pathogens have a highly restricted host range. An exception is the Gram-negative bacterium Pseudomonas aeruginosa, strains of which are pathogenic not only to humans but also to C. elegans, Drosophila, and the genetically tractable model plant, Arabidopsis thaliana (2, 3). In the December 21 issue of PNAS, Darby et al. (4) describe a genetic approach toward the identification of potential therapeutic targets for P. aeruginosa infection. P. aeruginosa is a common bacterium in soil and water worldwide and an opportunistic pathogen in humans, causing acute and chronic …