Novel Phenol-soluble Modulin Derivatives in Community-associated Methicillin-resistant Staphylococcus aureus Identified through Imaging Mass Spectrometry

Staphylococcus aureus causes a wide range of human disease ranging from localized skin and soft tissue infections to potentially lethal systemic infections. S. aureus has the biosynthetic ability to generate numerous virulence factors that assist in circumventing the innate immune system during dise...

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Bibliographic Details
Published in:The Journal of biological chemistry 2012-04, Vol.287 (17), p.13889-13898
Main Authors: Gonzalez, David J., Okumura, Cheryl Y., Hollands, Andrew, Kersten, Roland, Akong-Moore, Kathryn, Pence, Morgan A., Malone, Cheryl L., Derieux, Jaclyn, Moore, Bradley S., Horswill, Alexander R., Dixon, Jack E., Dorrestein, Pieter C., Nizet, Victor
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Anti-Infective Agents - pharmacology
Bacteria
Bacterial Infections
Bacterial Infections - metabolism
Bacterial Proteins - chemistry
Bacterial Toxins
Bacterial Toxins - chemistry
Erythrocytes - cytology
Hemolysis
Humans
Imaging Mass Spectrometry
Immunosuppressive Agents - pharmacology
Mass Spectrometry (MS)
Mass Spectrometry - methods
Metalloendopeptidases - chemistry
Methicillin-Resistant Staphylococcus aureus - metabolism
Mice
Microbiology
Molecular Sequence Data
Neutrophils - cytology
Neutrophils - metabolism
Phenol - chemistry
Phenol-soluble Modulins (PSMs)
Sequence Homology, Amino Acid
Sheep
Skin - metabolism
Skin - microbiology
Staphylococcal Skin Infections - microbiology
Staphylococcus aureus
Virulence Factors
Virulence Factors - chemistry
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Summary:Staphylococcus aureus causes a wide range of human disease ranging from localized skin and soft tissue infections to potentially lethal systemic infections. S. aureus has the biosynthetic ability to generate numerous virulence factors that assist in circumventing the innate immune system during disease pathogenesis. Recent studies have uncovered a set of extracellular peptides produced by community-associated methicillin-resistant S. aureus (CA-MRSA) with homology to the phenol-soluble modulins (PSMs) from Staphylococcus epidermidis. CA-MRSA PSMs contribute to skin infection and recruit and lyse neutrophils, and truncated versions of these peptides possess antimicrobial activity. In this study, novel CA-MRSA PSM derivatives were discovered by the use of microbial imaging mass spectrometry. The novel PSM derivatives are compared with their parent full-length peptides for changes in hemolytic, cytolytic, and neutrophil-stimulating activity. A potential contribution of the major S. aureus secreted protease aureolysin in processing PSMs is demonstrated. Finally, we show that PSM processing occurs in multiple CA-MRSA strains by structural confirmation of additional novel derivatives. This work demonstrates that IMS can serve as a useful tool to go beyond genome predictions and expand our understanding of the important family of small peptide virulence factors. Background: Phenol-soluble modulins (PSMs) are small peptides of Staphylococcus aureus with immunosuppressive and antimicrobial properties. Results: Imaging mass spectrometry (IMS) identified PSM derivatives with properties different from those of the parent forms. Conclusion:S. aureus generates truncated PSMs with altered antimicrobial and immunostimulatory properties and aureolysin may contribute to processing of some PSMs. Significance: Observations using the technology of IMS expand our understanding of S. aureus PSMs.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M112.349860