2. Academic Validation
  3. Towards Development of Small Molecule Lipid II Inhibitors as Novel Antibiotics

Towards Development of Small Molecule Lipid II Inhibitors as Novel Antibiotics

  • PLoS One. 2016 Oct 24;11(10):e0164515. doi: 10.1371/journal.pone.0164515.
Jamal Chauhan 1 2,  Steven Cardinale 3,  Lei Fang 1 4 2,  Jing Huang 1 4,  Steven M Kwasny 3,  M Ross Pennington 5,  Kelly Basi 5,  Robert diTargiani 5,  Benedict R Capacio 5,  Alexander D MacKerell Jr 1 4,  Timothy J Opperman 3,  Steven Fletcher 1,  Erik P H de Leeuw 6
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.
  • 2 Center for Biomolecular Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
  • 3 Microbiotix, Inc., One Innovation Drive, Worcester, Massachusetts, United States of America.
  • 4 Computer-Aided Drug Design Center, University of Maryland, School of Pharmacy, Baltimore, Maryland, United States of America.
  • 5 U.S. Army Medical Research Institute of Chemical Defense, Aberdeen Proving Ground, Maryland, United States of America.
  • 6 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.
PMID: 27776124 DOI: 10.1371/journal.pone.0164515
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.

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