Molecular Basis of Resistance to Muramidase and Cationic Antimicrobial Peptide Activity of Lysozyme in Staphylococci

PLoS Pathogens

Michael Meehl¹  Ambrose Cheung¹  Dirk Kraus²  Christiane Goerke²  Andreas Peschel²  Silvia Herbert³  Christiane Nerz³  Agnieszka Bera³  Friedrich Götz³ 

[1] Department of Microbiology, Dartmouth Medical School, Hanover, New Hampshire, United States of America;Medical Microbiology and Hygiene Department, University of Tübingen, Tübingen, Germany;Microbial Genetics Department, University of Tübingen, Tübingen, Germany

关键词: Staphylococcus aureus;    Polymyxins;    Gene regulation;    Regulator genes;    Operons;    Transcriptome analysis;    Deletion mutagenesis;    Antimicrobial resistance;   

DOI  :  10.1371/journal.ppat.0030102

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

It has been shown recently that modification of peptidoglycan by O-acetylation renders pathogenic staphylococci resistant to the muramidase activity of lysozyme. Here, we show that a Staphylococcus aureus double mutant defective in O-acetyltransferase A (OatA), and the glycopeptide resistance-associated two-component system, GraRS, is much more sensitive to lysozyme than S. aureus with the oatA mutation alone. The graRS single mutant was resistant to the muramidase activity of lysozyme, but was sensitive to cationic antimicrobial peptides (CAMPs) such as the human lysozyme-derived peptide 107R-A-W-V-A-W-R-N-R115 (LP9), polymyxin B, or gallidermin. A comparative transcriptome analysis of wild type and the graRS mutant revealed that GraRS controls 248 genes. It up-regulates global regulators (rot, sarS, or mgrA), various colonization factors, and exotoxin-encoding genes, as well as the ica and dlt operons. A pronounced decrease in the expression of the latter two operons explains why the graRS mutant is also biofilm-negative. The decrease of the dlt transcript in the graRS mutant correlates with a 46.7% decrease in the content of esterified d-alanyl groups in teichoic acids. The oatA/dltA double mutant showed the highest sensitivity to lysozyme; this mutant completely lacks teichoic acid–bound d-alanine esters, which are responsible for the increased susceptibility to CAMPs and peptidoglycan O-acetylation. Our results demonstrate that resistance to lysozyme can be dissected into genes mediating resistance to its muramidase activity (oatA) and genes mediating resistance to CAMPs (graRS and dlt). The two lysozyme activities act synergistically, as the oatA/dltA or oatA/graRS double mutants are much more susceptible to lysozyme than each of the single mutants.

【 授权许可】

CC BY