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Diglycine Enables Rapid Intrabacterial Hydrolysis for Activating Anbiotics against Gram‐negative Bacteria
Author(s) -
Wang Jiaqing,
Cooper Deani L.,
Zhan Wenjun,
Wu Difei,
He Hongjian,
Sun Shenghuan,
Lovett Susan T.,
Xu Bing
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201905230
Subject(s) - prodrug , chemistry , chloramphenicol , antibiotics , escherichia coli , hydrolysis , antimicrobial , combinatorial chemistry , cytotoxicity , bacteria , conjugate , biochemistry , stereochemistry , organic chemistry , in vitro , biology , mathematical analysis , genetics , mathematics , gene
Antimicrobial drug resistance demands novel approaches for improving the efficacy of antibiotics, especially against Gram‐negative bacteria. Herein, we report that conjugating a diglycine (GG) to an antibiotic prodrug drastically accelerates intrabacterial ester‐bond hydrolysis required for activating the antibiotic. Specifically, the attachment of GG to chloramphenicol succinate (CLsu) generates CLsuGG, which exhibits about an order of magnitude higher inhibitory efficacy than CLsu against Escherichia coli . Further studies reveal that CLsuGG undergoes rapid hydrolysis, catalyzed by intrabacterial esterases (e.g., BioH and YjfP), to generate chloramphenicol (CL) in E. coli . Importantly, the conjugate exhibits lower cytotoxicity to bone marrow stromal cells than CL. Structural analogues of CLsuGG indicate that the conjugation of GG to an antibiotic prodrug is an effective strategy for accelerating enzymatic prodrug hydrolysis and enhancing the antibacterial efficacy of antibiotics.