Optimization of a small-molecule Lipid II binder. Issue 14 (15th July 2019)

• Record Type: Journal Article
• Authors: Chauhan, Jay; Kwasny, Steven M.; Fletcher, Steven; Opperman, Timothy J.; de Leeuw, Erik P.H.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 14(2019)
• Page Start: 1849
• Page End: 1853
• Publication Date: 2019-07-15
• Subjects: S. aureus Staphylococcus aureus -- E. faecium Enterococcus faecium -- MIC minimal inhibitory concentration -- MurNAc N-acetyl muramic acid; Lipid II -- Antibiotics -- Drug development; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2019.04.046
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Lipid II is an essential precursor of bacterial cell wall biosynthesis and an attractive target for antibiotics. Lipid II is comprised of specialized lipid (bactoprenol) linked to a hydrophilic head group consisting of a peptidoglycan subunit ( N -acetylglucosamine (GlcNAc)- N -acetylmuramic acid (MurNAc) disaccharide coupled to a short pentapeptide moiety) via a pyrophosphate. We previously identified a ( E )-2, 4-bis(4-bromophenyl)-6-(4-(dimethylamino)styryl)pyrylium boron tetrafluoride salt, termed 6jc48-1, that interacts with the MurNAc moiety, the phosphate cage and the isoprenyl tail of Lipid II. Here, we report on the structure-activity relationship of 6jc48-1 derivatives obtained by de novo chemical synthesis. Our results indicate that bacterial killing is positively driven by bi-phenyl stacking with peptidoglycan units. Replacement of bromides by fluorides resulted in activity against S. aureus without affecting Lipid II binding and cytotoxicity. Antibacterial activity was affected negatively by extended interaction of the scaffold with Lipid II isoprenyl units.