L-Rhamnosylation of Listeria Monocytogenes Wall Teichoic Acids Promotes Resistance to Antimicrobial Peptides by Delaying Interaction With the Membrane

PLoS Pathog. 2015 May 22;11(5):e1004919. doi: 10.1371/journal.ppat.1004919. eCollection 2015 May.

Abstract

Listeria monocytogenes is an opportunistic Gram-positive bacterial pathogen responsible for listeriosis, a human foodborne disease. Its cell wall is densely decorated with wall teichoic acids (WTAs), a class of anionic glycopolymers that play key roles in bacterial physiology, including protection against the activity of antimicrobial peptides (AMPs). In other Gram-positive pathogens, WTA modification by amine-containing groups such as D-alanine was largely correlated with resistance to AMPs. However, in L. monocytogenes, where WTA modification is achieved solely via glycosylation, WTA-associated mechanisms of AMP resistance were unknown. Here, we show that the L-rhamnosylation of L. monocytogenes WTAs relies not only on the rmlACBD locus, which encodes the biosynthetic pathway for L-rhamnose, but also on rmlT encoding a putative rhamnosyltransferase. We demonstrate that this WTA tailoring mechanism promotes resistance to AMPs, unveiling a novel link between WTA glycosylation and bacterial resistance to host defense peptides. Using in vitro binding assays, fluorescence-based techniques and electron microscopy, we show that the presence of L-rhamnosylated WTAs at the surface of L. monocytogenes delays the crossing of the cell wall by AMPs and postpones their contact with the listerial membrane. We propose that WTA L-rhamnosylation promotes L. monocytogenes survival by decreasing the cell wall permeability to AMPs, thus hindering their access and detrimental interaction with the plasma membrane. Strikingly, we reveal a key contribution of WTA L-rhamnosylation for L. monocytogenes virulence in a mouse model of infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Infective Agents / pharmacology
  • Antimicrobial Cationic Peptides / pharmacology*
  • Cell Membrane / metabolism*
  • Cell Wall / metabolism*
  • Cells, Cultured
  • Drug Resistance, Bacterial / drug effects*
  • Glycosylation
  • Humans
  • Listeria monocytogenes / physiology*
  • Listeriosis / drug therapy
  • Listeriosis / microbiology*
  • Macrophages / drug effects
  • Macrophages / microbiology
  • Mice
  • Mice, Inbred BALB C
  • Rhamnose / chemistry*
  • Teichoic Acids / pharmacology*
  • Virulence

Substances

  • Anti-Infective Agents
  • Antimicrobial Cationic Peptides
  • Teichoic Acids
  • Rhamnose