Semisynthetic Development of Blasticidin S as an Antibiotic Lead and Development of Other Anti-Infectives

Abstract

Recent decades have seen a decline in discovery of new classes of antibiotics. This lack of new antibiotics is punctuated by the spread of antibiotic resistance and has placed society in a global health crisis. To mitigate the potentially devastating effects of widespread antibiotic resistance, new classes of antibiotics capable of killing resistant bacteria must be developed and deployed; yet the lack of new classes of antibacterial compounds found through traditional discovery methods has left many wondering where new antibiotics will come from. A potentially rich source of new classes of antibacterial compounds is the forgotten natural product antimicrobials, many of which have unique mechanisms of action effective against resistant bacteria. In this dissertation, we describe modification of one such forgotten compound, the broad-spectrum, translation inhibitor, blasticidin S. We produced three series of semisynthetic derivatives of blasticidin S that show a marked increase in antibacterial activity against gram-positive bacteria and an increase in selectivity index for pathogenic bacteria over human cells. Our best derivatives increased the antibacterial activity up to 32-fold versus blasticidin S, resulting in MIC's as low as 4 g/mL. The selectivity indices for our derivatives likewise improved, from <1 (for BLS) up to 26. This work demonstrates that semisynthetic derivatization of forgotten natural product antimicrobials can increase their activity against and selectivity for bacteria, an approach that can be leveraged for the development of antibiotic leads to fight resistant pathogens. Also presented is work on new computationally identified and optimized antiviral drugs and the future directions of these projects.