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Effect of a small molecule Lipid II binder on bacterial cell wall stress

Authors Malin J, Shetty AC, Daugherty SC, de Leeuw EPH

Received 1 November 2016

Accepted for publication 20 December 2016

Published 28 February 2017 Volume 2017:10 Pages 69—73

DOI https://doi.org/10.2147/IDR.S126254

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 3

Editor who approved publication: Professor Suresh Antony

Jakob Malin,1,2 Amol C Shetty,3 Sean Daugherty,3 Erik PH de Leeuw,1,2

1Institute of Human Virology, 2Department of Biochemistry and Molecular Biology, 3Institute for Genome Sciences, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA


Abstract: We have recently identified small molecule compounds that act as binders of Lipid II, an essential precursor of bacterial cell wall biosynthesis. Lipid II comprised a hydrophilic head group that includes a peptidoglycan subunit composed of N-acetylglucosamine (GlcNAc) and N-acetylmuramic acid (MurNAc) coupled to a short pentapeptide moiety. This headgroup is coupled to a long bactoprenol chain via a pyrophosphate group. Here, we report on the cell wall activity relationship of dimethyl-3-methyl(phenyl)amino-ethenylcyclohexylidene-propenyl-3-ethyl-1,3-benzothiazolium iodide (compound 5107930) obtained by functional and genetic analyses. Our results indicate that compounds bind to Lipid II and cause specific upregulation of the vancomycin-resistance associated gene vraX. vraX is implicated in the cell wall stress stimulon that confers glycopeptide resistance. Our small molecule Lipid II inhibitor retained activity against strains of Staphylococcus aureus mutated in genes encoding the cell wall stress stimulon. This suggests the feasibility of developing this new scaffold as a therapeutic agent in view of increasing glycopeptide resistance.

Keywords: defensin, Lipid II, antibiotics, bacterial membrane, vancomycin

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