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

Le résumé fourni par la source

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.

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