title: Towards Development of Small Molecule Lipid II Inhibitors as Novel Antibiotics.
abstract: Recently we described a novel di-benzene-pyrylium-indolene (BAS00127538) inhibitor of Lipid II. BAS00127538 (1-Methyl-2,4-diphenyl-6-((1E,3E)-3-(1,3,3-trimethylindolin-2-ylidene)prop-1-en-1-yl)pyryl-1-ium) tetrafluoroborate is the first small molecule Lipid II inhibitor and is structurally distinct from natural agents that bind Lipid II, such as vancomycin. Here, we describe the synthesis and biological evaluation of 50 new analogs of BAS00127538 designed to explore the structure-activity relationships of the scaffold. The results of this study indicate an activity map of the scaffold, identifying regions that are critical to cytotoxicity, Lipid II binding and range of anti-bacterial action. One compound, 6jc48-1, showed significantly enhanced drug-like properties compared to BAS00127538. 6jc48-1 has reduced cytotoxicity, while retaining specific Lipid II binding and activity against Enterococcus spp. in vitro and in vivo. Further, this compound showed a markedly improved pharmacokinetic profile with a half-life of over 13 hours upon intravenous and oral administration and was stable in plasma. These results suggest that scaffolds like that of 6jc48-1 can be developed into small molecule antibiotic drugs that target Lipid II.
authors: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors: Jamal
authors: J
authors: Chauhan
authors: Microbiotix, Inc., One Innovation Drive, Worcester, Massachusetts, United States of America.
authors: Steven
authors: S
authors: Cardinale
authors: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.|Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.|Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
authors: Lei
authors: L
authors: Fang
authors: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.|Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.
authors: Jing
authors: J
authors: Huang
authors: Microbiotix, Inc., One Innovation Drive, Worcester, Massachusetts, United States of America.
authors: Steven M
authors: SM
authors: Kwasny
authors: U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America.
authors: M Ross
authors: MR
authors: Pennington
authors: U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America.
authors: Kelly
authors: K
authors: Basi
authors: U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America.
authors: Robert
authors: R
authors: diTargiani
authors: U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America.
authors: Benedict R
authors: BR
authors: Capacio
authors: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.|Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.
authors: Alexander D
authors: AD
authors: MacKerell
authors: Microbiotix, Inc., One Innovation Drive, Worcester, Massachusetts, United States of America.
authors: Timothy J
authors: TJ
authors: Opperman
authors: Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.
authors: Steven
authors: S
authors: Fletcher
authors: Institute of Human Virology & Department of Biochemistry and Molecular Biology of the University of Maryland Baltimore School of Medicine, Baltimore, Maryland, United States of America.
authors: Erik P H
authors: EP
authors: de Leeuw
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001798:Blood Proteins / Q000378:metabolism; D006801:Humans; D008055:Lipids / Q000037:antagonists & inhibitors*; D051379:Mice; D008826:Microbial Sensitivity Tests; D008862:Microsomes, Liver / Q000187:drug effects; D056004:Molecular Dynamics Simulation; D020349:Surface Plasmon Resonance
chemical_list: D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D008055:Lipids