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Mol Inform. 2018 Jul;37(6-7):e1800004. doi: 10.1002/minf.201800004. Epub 2018 Mar 8.

In silico Predicted Glucose-1-phosphate Uridylyltransferase (GalU) Inhibitors Block a Key Pathway Required for Listeria Virulence.

Author information

1
Department of Chemistry, Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA.
2
Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA.

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.

KEYWORDS:

antibiotics; drug design; molecular modeling; structure-activity relationships; virtual screening

PMID:
29517123
DOI:
10.1002/minf.201800004
[Indexed for MEDLINE]

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