| In the last three decades there has been a consistent increase in the number of antimicrobial resistant pathogens with a concomitant decline in the number of new antibiotic drugs available to treat them. One potential solution to this escalating concern is to develop new classes of antibiotics that have novel mechanisms of action, since drugs that fit these criteria will be exempt from contemporary modes of antimicrobial resistance. To this end, we propose essential tRNA modifications lysidine (k2C34) and N6-threonylcarbamoyl adenosine (t6A37) as potential targets for new classes of antibiotic drugs. We describe the development of two types of compounds designed to inhibit the biosynthesis of lysidine, namely lysine pseudo-substrates and lysine-AMP multi-substrate analogs. In addition, we report a synthetic route for the total synthesis of lysidine and its functional analog in archaea, agmatidine, such that their properties may be studied to elucidate future rational antimicrobial strategies based on their function. Finally, we detail our attempts to inhibit the biosynthesis of t6A37 by creating analogs of known biosynthesis intermediate TC-AMP. In conjunction, these projects constitute an attempt to analyze these tRNA modifications so that they may be realized as antimicrobial targets in the future. |
