Late‐Stage Functionalization of Glucosides and Aminoglycosides to Combat Resistant Resistance

The rapid emergence of resistant bacteria and the scarcity of the antibiotic pipeline have been a persistent threat to global health. To expand the antibiotic pipeline,the strategy has focused on revitalizing the current antibiotic via novel site-specific derivatization. Aminoglycosides (AGs), once considered effective therapeutics for treating clinical infections, are now used to a limited extent due to drug-induced toxicity and AG-resistant bacteria. Challenges in the synthesis and modification of AGs impede their potential for regain efficacy. Herein, a photoredox catalyzed late-stage modification of glucosides including AGs is discussed. The chemistry can selectively install an alkyl group at the 3-position of unprotected glucoside with a broad substrate scope and high yields. Among the products, a series of compounds are characterized that can overcome drug resistance caused by APH(3') and one of them achieves 30-fold potency compared to kanamycin against sensitive strains. The chemistry described here opens a new avenue for discovering new AG antibiotics that overcome drug resistance and may also serve as the basis for understanding their structure-activity relationships.