title: Effect of a small molecule Lipid II binder on bacterial cell wall stress.
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 ofN-acetylglucosamine (GlcNAc) andN-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 genevraX.vraXis implicated in the cell wall stress stimulon that confers glycopeptide resistance. Our small molecule Lipid II inhibitor retained activity against strains ofStaphylococcus aureusmutated 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.
authors.affiliation: Institute of Human Virology; Department of Biochemistry and Molecular Biology.
authors.forename: Jakob
authors.initials: J
authors.lastname: Malin
authors.affiliation: Institute for Genome Sciences, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA.
authors.forename: Amol C
authors.initials: AC
authors.lastname: Shetty
authors.affiliation: Institute for Genome Sciences, University of Maryland Baltimore School of Medicine, Baltimore, MD, USA.
authors.forename: Sean C
authors.initials: SC
authors.lastname: Daugherty
authors.affiliation: Institute of Human Virology; Department of Biochemistry and Molecular Biology.
authors.forename: Erik Ph
authors.initials: EP
authors.lastname: de Leeuw
keywords: Lipid II; antibiotics; bacterial membrane; defensin; vancomycin