The Principal Investigator proposes to develop new antibiotics based on the inhibition of pathogen protein synthesis through a previously unexplored mechanism. The aminoacyl tRNA synthetases (AARS), a family of enzymes that catalyze the first step of protein translation, will be targeted. The investigators propose to exploit the significant selectivity shown between mammalian and pathogen cells exhibited by lead structures that have been selected for the study. This will provide the requirements to achieve species specific inhibition and, therefore, minimize toxicity to human cells. The goals of the proposal include: 1) To develop inhibitors of isoleucyl tRNA synthetase with improved stability, potency and expanded antibacterial spectrum suitable for oral or intra venous route of administration, 2) To probe the binding mode of PMA-A and isolecinol adenylate to isoleucyl tRNA synthetase through rationally designed hybrid molecules. The synthetic compounds will be tested in vitro to determine potency. The active compounds will then be tested against a range of bacterial and fungal pathogens in a whole cell assay. The investigators will also specifically test for activities against Mycobacterium tuberculosis and Pneumocystis carinii.
