Chemistry Seminar with Dr. Andrew Lowell from Virginia Tech at 4:00pm

Abstract:

Of the more than 200 million antibiotic prescriptions dispensed annually in the US, the vast majority are semisynthetic derivatives of natural products. The rise of antimicrobial resistant pathogens (>1.2 million deaths worldwide in 2019) drives continued semisynthetic development of existing antibiotic scaffolds, especially in the absence of reliable new antimicrobial discovery.   To meet the need for effective antibiotics, our collaborative team uses structure-based and computer-aided drug design to rationally modify natural products. This approach is focused on two areas: 1) refinement of established antibiotics and 2) development of forgotten antimicrobials into new antibiotics. 

Pleuromutilins, the most recently approved antibiotic class for systemic human use, are promising for continued development because bacteria develop resistance to them slowly.  However, all commercial pleuromutilins are modified only in one place, at the primary alcohol of the glycolate ester. An iterative series of semisynthesis and computational modeling enabled identification and development of another modification site, the vinyl group on the mutilin core. Epimerization followed by an anti-Markovnikov hydroazidation reaction and subsequent copper-catalyzed azido-alkyne cycloaddition reactions achieved libraries of triazole derivatives that showed up to 8-fold enhancement in antimicrobial activity. Computational modeling suggests that the top derivatives access new regions of the ribosome target, setting the stage for additional development. Furthermore, the presence or absence of a functionalized glycolate ester did not affect activity, suggesting that optimizing this position could lead to compounds with even greater potency.   

Forgotten antimicrobials are undeveloped natural products that are a potentially rich source of antibiotics. This surprisingly large group of molecules were previously identified but deprioritized in favor of more tractable compounds. Their composition ranges from structurally unknown isolates to well-characterized molecules with high activity and new mechanisms of inhibition. We are developing these molecules by studying their biosynthesis (thermorubin) and by implementing a judicious combination of semisynthesis and computational modeling (blasticidin S) to improve their antibiotic properties. 

Combined, these approaches lay the groundwork for improving current antibiotics and for developing completely new drugs. Activity findings serve as starting points for continued computational modeling and derivatization. Top compounds are undergoing testing as antibiotics against antimicrobial resistant pathogens in animal models.