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 of N-acetylglucosamine (GlcNAc) and N-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 gene vraX. vraX is implicated in the cell wall stress stimulon that confers glycopeptide resistance. Our small molecule Lipid II inhibitor retained activity against strains of Staphylococcus aureus mutated 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.

Keywords:

• defensin
• Lipid II
• antibiotics
• bacterial membrane
• vancomycin

Acknowledgments

The authors gratefully acknowledge Drs Maria Senn and Chantal Qublier of the Institute for Medicinal Chemistry, University of Zurich, Switzerland, for providing the bacterial strains carrying mutations in the cell wall stress stimulon. This work was supported by National Institutes of Health grant AI092033 and a University of Maryland Ventures grant to EPHdL.

Disclosure

The authors report the following competing interests: US patent number 8,796,323 and US nonprovisional patent application number 13/911,234. The authors report no other conflicts of interest in this work.