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Harnessing Endogenous Formate for Antibacterial Prodrug Activation by in cellulo Ruthenium‐Mediated Transfer Hydrogenation Reaction
Author(s) -
Weng Cheng,
Shen Linghui,
Ang Wee Han
Publication year - 2020
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.202000173
Subject(s) - prodrug , formate , chemistry , combinatorial chemistry , bacteria , ruthenium , antibacterial activity , azide , bioproduction , catalysis , biochemistry , biology , organic chemistry , genetics
The abundance and evolving pathogenic behavior of bacterial microorganisms give rise to antibiotic tolerance and resistance which pose a danger to global public health. New therapeutic strategies are needed to keep pace with this growing threat. We propose a novel approach for targeting bacteria by harnessing formate, a cell metabolite found only in particular bacterial species, to activate an antibacterial prodrug and selectively inhibit their growth. This strategy is premised on transfer hydrogenation reaction on a biorthogonal substrate utilizing native formate as the hydride source as a means of uncaging an antibacterial prodrug. Using coordination‐directed 3‐component assembly to prepare a library of 768 unique Ru–Arene Schiff‐base complexes, we identified several candidates that efficiently reduced sulfonyl azide functional group in the presence of formate. This strategy paves the way for a new approach of targeted antibacterial therapy by exploiting unique bacterial metabolites.