Organic Chemistry

Late-stage functionalization of glucosides and aminoglycosides to combat resistant pathogens

Authors

Abstract

The rapid emergence of resistant bacteria and the scarcity of antibiotic pipeline has been a persistent threat to the global health. To expand the antibiotic pipeline, we have focused our strategy by revitalizing the current antibiotic via novel site-specific derivatization. Aminoglycosides (AGs), once considered effective therapeutics for treating clinical infections, are now seeing limited use due to drug-induced toxicity and AG-resistant bacteria. Challenges in synthesis and modifications of AGs impedes their potential for re-gaining efficacy. Here we discuss a photoredox catalyzed late-stage modification of glucosides including AGs. Our 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, we characterized a series of compounds that can overcome drug resistance caused by APH (3’) and one of them achieved 30-fold potency compared to kanamycin against sensitive strains. The chemistry we describe here opens a new avenue for discovering new AGs antibiotics that overcome drug resistance and may also serve as the basis for understanding their SARs.

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the structure and HRMS of amikacin

Content

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Supplementary material

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Late-stage functionalization of glucosides and aminoglycosides to combat resistant pathogens
Supplementary Material for "Late-stage functionalization of glucosides and aminoglycosides to combat resistant pathogens"