title: Structure-activity exploration of a small-molecule Lipid II inhibitor.
abstract: We have recently identified low-molecular weight compounds that act as inhibitors of Lipid II, an essential precursor of bacterial cell wall biosynthesis. Lipid II comprises specialized lipid (bactoprenol) linked to a hydrophilic head group consisting of a peptidoglycan subunit (N-acetyl glucosamine [GlcNAc]-N-acetyl muramic acid [MurNAc] disaccharide coupled to a short pentapeptide moiety) via a pyrophosphate. One of our lead compounds, a diphenyl-trimethyl indolene pyrylium, termed BAS00127538, interacts with the MurNAc moiety and the isoprenyl tail of Lipid II. Here, we report on the structure-activity relationship of BAS00127538 derivatives obtained by in silico analyses and de novo chemical synthesis. Our results indicate that Lipid II binding and bacterial killing are related to three features: the diphenyl moiety, the indolene moiety, and the positive charge of the pyrylium. Replacement of the pyrylium moiety with an N-methyl pyridinium, which may have importance in stability of the molecule, did not alter Lipid II binding or antibacterial potency.
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Fletcher
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA ; Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Yu
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA ; Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Huang
authors.affiliation: Microbiotix, Inc., Worcester, MA, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Kwasny
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
authors.forename: Jay
authors.initials: J
authors.lastname: Chauhan
authors.affiliation: Microbiotix, Inc., Worcester, MA, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Opperman
authors.affiliation: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, MD, USA ; Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, MD, USA.
authors.forename: Alexander D
authors.initials: AD
authors.lastname: MacKerell
authors.affiliation: Institute of Human Virology and Department of Biochemistry and Molecular Biology, University of Maryland, School of Medicine, Baltimore, MD, USA.
authors.forename: Erik  P H
authors.initials: E
authors.lastname: de Leeuw
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D011714:Pyrans / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014538:Uridine Diphosphate N-Acetylmuramic Acid / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors
chemical_list: D000900:Anti-Bacterial Agents; C000597298:BAS00127538; D007211:Indoles; D011714:Pyrans; D054852:Small Molecule Libraries; D014538:Uridine Diphosphate N-Acetylmuramic Acid; C069249:muramyl-NAc-(pentapeptide)pyrophosphoryl-undecaprenol
keywords: Lipid II; antibiotics; computer-aided drug design; phospholipid