Sugar-based bactericides targeting phosphatidylethanolamine-enriched membranes

Nat Commun. 2018 Nov 19;9(1):4857. doi: 10.1038/s41467-018-06488-4.

Abstract

Anthrax is an infectious disease caused by Bacillus anthracis, a bioterrorism agent that develops resistance to clinically used antibiotics. Therefore, alternative mechanisms of action remain a challenge. Herein, we disclose deoxy glycosides responsible for specific carbohydrate-phospholipid interactions, causing phosphatidylethanolamine lamellar-to-inverted hexagonal phase transition and acting over B. anthracis and Bacillus cereus as potent and selective bactericides. Biological studies of the synthesized compound series differing in the anomeric atom, glycone configuration and deoxygenation pattern show that the latter is indeed a key modulator of efficacy and selectivity. Biomolecular simulations show no tendency to pore formation, whereas differential metabolomics and genomics rule out proteins as targets. Complete bacteria cell death in 10 min and cellular envelope disruption corroborate an effect over lipid polymorphism. Biophysical approaches show monolayer and bilayer reorganization with fast and high permeabilizing activity toward phosphatidylethanolamine membranes. Absence of bacterial resistance further supports this mechanism, triggering innovation on membrane-targeting antimicrobials.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / pharmacology*
  • Bacillus anthracis / chemistry
  • Bacillus anthracis / drug effects*
  • Bacillus anthracis / growth & development
  • Bacillus anthracis / metabolism
  • Bacillus cereus / chemistry
  • Bacillus cereus / drug effects*
  • Bacillus cereus / growth & development
  • Bacillus cereus / metabolism
  • Caco-2 Cells
  • Carbohydrate Conformation
  • Cell Membrane / chemistry
  • Cell Membrane / drug effects*
  • Cell Membrane / metabolism
  • Cell Survival / drug effects
  • Cell Wall / chemistry
  • Cell Wall / drug effects*
  • Cell Wall / metabolism
  • Glycosides / pharmacology*
  • Humans
  • Kinetics
  • Lipid Bilayers / chemistry
  • Lipid Bilayers / metabolism
  • Microbial Sensitivity Tests
  • Microbial Viability / drug effects
  • Phase Transition
  • Phosphatidylethanolamines / antagonists & inhibitors*
  • Phosphatidylethanolamines / chemistry
  • Phosphatidylethanolamines / metabolism
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Glycosides
  • Lipid Bilayers
  • Phosphatidylethanolamines