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In silico Predicted Glucose‐1‐phosphate Uridylyltransferase (GalU) Inhibitors Block a Key Pathway Required for Listeria Virulence
Author(s) -
Kuenemann Melaine A.,
Spears Patricia A.,
Orndorff Paul E.,
Fourches Denis
Publication year - 2018
Publication title -
molecular informatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.481
H-Index - 68
eISSN - 1868-1751
pISSN - 1868-1743
DOI - 10.1002/minf.201800004
Subject(s) - virulence , teichoic acid , in silico , listeria monocytogenes , listeria , biochemistry , chemistry , peptidoglycan , microbiology and biotechnology , bacteria , biology , enzyme , genetics , gene
Abstract Peptidoglycan walls of gram positive bacteria are functionalized by glycopolymers called wall teichoic acid (WTA). In Listeria monocytogenes , multiple enzymes including the glucose‐1‐phosphate uridylyltransferase (GalU) were identified as mandatory for WTA galactosylation, so that the inhibition of GalU is associated with a significant attenuation of Listeria virulence. Herein, we report on a series of in silico predicted GalU inhibitors identified using structure‐based virtual screening and experimentally validated to be effective in blocking the WTA galactosylation pathway in vitro . Several hits such as C04, a pyrimidinyl benzamide, afforded promising experimental potencies. This proof‐of‐concept study opens new perspectives for the development of potent and selective GalU inhibitors of high interest to attenuate Listeria virulence. It also underscores the high relevance of using molecular modeling for facilitating the identification of bacterial virulence attenuators and more generally antibacterials.