Molecular basis of resistance to muramidase and cationic antimicrobial peptide activity of lysozyme in staphylococci

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Silvia Herbert1, Agnieszka Bera, Christiane Nerz

  • 1Microbial Genetics Department, University of Tübingen, Tübingen, Germany.

Plos Pathogens
|August 7, 2007
PubMed

Insights

Staphylococcus aureus resistance to lysozyme involves two key mechanisms: O-acetylation (oatA) for muramidase activity and GraRS/dlt for cationic antimicrobial peptide resistance. Double mutants lacking both show synergistic susceptibility to lysozyme.

Area of Science:

  • Microbiology
  • Bacterial Pathogenesis
  • Molecular Biology

Background:

  • Pathogenic staphylococci can resist lysozyme via peptidoglycan O-acetylation.
  • Lysozyme exhibits both muramidase and cationic antimicrobial peptide (CAMP) activities.
  • The role of the GraRS two-component system in lysozyme resistance is not fully understood.

Purpose of the Study:

  • To investigate the distinct roles of O-acetyltransferase A (OatA) and the GraRS system in Staphylococcus aureus resistance to lysozyme.
  • To elucidate the genetic basis of lysozyme resistance by analyzing gene expression changes in a graRS mutant.
  • To determine the synergistic effects of mutations in oatA, graRS, and dlt on lysozyme susceptibility.

Main Methods:

  • Construction and characterization of Staphylococcus aureus mutants (oatA, graRS, oatA/graRS, oatA/dltA).
  • Lysozyme susceptibility assays.
  • Comparative transcriptome analysis (RNA sequencing) of wild-type and graRS mutant strains.
  • Quantification of d-alanyl ester content in teichoic acids.

Main Results:

  • A graRS single mutant showed increased sensitivity to CAMPs but retained resistance to lysozyme's muramidase activity.
  • The graRS mutant exhibited significant downregulation of the ica and dlt operons, leading to biofilm-negativity and reduced d-alanyl esters in teichoic acids.
  • The oatA/dltA double mutant, lacking d-alanyl esters, displayed the highest sensitivity to lysozyme, indicating synergistic effects with oatA mutations.

Conclusions:

  • Lysozyme resistance in Staphylococcus aureus is mediated by distinct genetic pathways: oatA for muramidase activity and graRS/dlt for CAMP resistance.
  • GraRS regulates key virulence factors, including biofilm formation and cell wall modifications (dlt operon).
  • Combined disruption of oatA and graRS or dlt significantly enhances susceptibility to lysozyme, highlighting synergistic interactions.

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