Aminoacyl tRNA synthetases as targets for antibiotic development

Abstract

Aminoacyl tRNA synthetases represent drug targets against which numerous small molecule natural products are available for further development into useful antibiotics. An understanding of the chemical properties, characterization of mode of action, and the elucidation of biosynthetic mechanisms for these molecules is necessary for the design of derivatives with enhanced pharmacological properties. Despite the ubiquity of small molecule natural products that inhibit tRNA synthetases, only a very small number of these compounds have been approved for clinical use. Here, we focus our discussion on tRNA synthetase inhibitor molecules of three different chemical classes, namely those derived from polyketide precursors, those that occur as phosphoramidate conjugates, and promising synthetic molecules with a mode of action that is distinct from molecules of the first two classes. Also discussed are the factors that undermine the broad-based use of some of these molecules as effective antibiotics in humans and strategies that may aid in directing the development of derivatives with improved pharmacological properties.