Activity of<i>Staphylococcus epidermidis</i>Phenol‐Soluble Modulin Peptides Expressed in<i>Staphylococcus carnosus</i>

Otto, Michael; O'Mahoney, D. Shane; Guina, Tína; Klebanoff, Seymour J.

doi:10.1086/422157

Cited by 32 publications

(22 citation statements)

References 24 publications

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“…PSMs are cytolytic against several host cell types, a quality that contributes to S. aureus infection (12,18). Cytotoxicity is attributed to PSM peptides found as soluble species in the supernatants of liquid cultures (51,52). Thus, we used LC-MS-MS to verify that N-AgrD is also found in culture supernatants.…”

Section: Resultsmentioning

confidence: 99%

The AgrD N-Terminal Leader Peptide of Staphylococcus aureus Has Cytolytic and Amyloidogenic Properties

et al. 2014

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Staphylococcus aureus virulence is coordinated through the Agr quorum-sensing system to produce an array of secreted molecules. One important class of secreted virulence factors is the phenol-soluble modulins (PSMs). PSMs are small-peptide toxins that have recently been characterized for their roles in infection, biofilm development, and subversion of the host immune system. In this work, we demonstrate that the signal peptide of the S. aureus quorum-sensing signal, AgrD, shares structural and functional similarities with the PSM family of toxins. The efficacy of this peptide (termed N-AgrD) beyond AgrD propeptide trafficking has never been described before. We observe that N-AgrD, like the PSMs, is found in the amyloid fibrils of S. aureus biofilms and is capable of forming and seeding amyloid fibrils in vitro. N-AgrD displays cytolytic and proinflammatory properties that are abrogated after fibril formation. These data suggest that the N-AgrD leader peptide affects S. aureus biology in a manner similar to that described previously for the PSM peptide toxins. Taken together, our findings suggest that peptide cleavage products can affect cellular function beyond their canonical roles and may represent a class of virulence factors warranting further exploration.

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Section: Resultsmentioning

confidence: 99%

The AgrD N-Terminal Leader Peptide of Staphylococcus aureus Has Cytolytic and Amyloidogenic Properties

et al. 2014

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“…Synthetic Peptides PSM peptides with the recently published sequences [13][14][15]17] , the FPR2/ALX-specific control ligand MMK1 (LESIFRSLL-FRVM-NH2) [32] and the FPR2/ALX inhibitor WRW4 (WRW-WWW-NH2) [33,34] were synthesized (EMC Microcollections). The peptides were synthesized using solid-phase Fmoc/tBu chemistry.…”

Section: Methodsmentioning

confidence: 99%

“…S. epidermidis infections develop only rarely into life-threatening diseases, but they are often difficult to eradicate because of antibiotic resistance genes and the formation of biofilms [12,13] . PSMs were initially identified in S. epidermidis culture filtrates [13][14][15] . Related peptides have subsequently been described in S. aureus [16,17] and, only recently, in virtually all staphylococcal pathogens [18] .…”

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confidence: 99%

The Virulence Regulator Agr Controls the Staphylococcal Capacity to Activate Human Neutrophils via the Formyl Peptide Receptor 2

Kretschmer

Nikola²,

Dürr³

et al. 2011

J Innate Immun

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The Agr quorum-sensing system represents the master regulator for staphylococcal virulence factors and is known to have a strong impact on the release of pathogen-associated molecular pattern (PAMP) molecules. Among the various staphylococcal PAMPs, phenol-soluble modulin (PSM) peptides have attracted increasing interest because they are crucial for staphylococcal virulence and have neutrophil-recruiting properties. The latter depend on recognition of PSMs by the neutrophil formyl peptide receptor 2 (FPR2/ALX), for which PSMs are highly efficient agonists. We demonstrate that Agr inactivation in Staphylococcus aureus or S. epidermidis leads to strongly reduced neutrophil responses, which is in agreement with the previously reported strict control of PSM expression by Agr. Agr had a distinct and profound impact on activation of FPR2/ALX but not of the related FPR1 receptor that senses bacterial formylated peptides. S. epidermidis PSMs had similar FPR2/ALX-activating properties but differed in their dependence on N-terminal formylation compared to S. aureus PSMs. Moreover, S. aureus and S. epidermidis PSMs upregulated the neutrophil complement receptor CD11b via FPR2/ALX stimulation in an Agr-dependent fashion. Hence, Agr controls the capacity of staphylococcal pathogens to activate FPR2/ALX-dependent neutrophil responses, underscoring the crucial role of FPR2/ALX and PSMs in staphylococcus-host interaction.

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“…Indeed, others have also observed an inverse relationship between biofilm formation and expression of the RNAIII transcript, which includes the phenol-soluble modulin (PSM) d-toxin (hld) (Vuong et al, 2000). PSMs are surfactant-like peptides that have pro-inflammatory properties, and a role in the detachment of biofilms, in Staphylococcus epidermidis (Mehlin et al, 1999;Otto et al, 2004;Vuong et al, 2004;Yao et al, 2005). In addition to dtoxin (hld) itself, we also found that expression of another *ER, expression ratio: the normalized microarray signal intensity value for the UAMS-1 agr mutant divided by that for wild-type UAMS-1.…”

Section: Transcriptional Profiling Of the Uams-1 Agr Regulonmentioning

confidence: 99%

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

Cassat

Dunman

Murphy³

et al. 2006

Microbiology

147

157

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The production of Staphylococcus aureus virulence factors is under the control of complex regulatory circuits. Most studies aimed at defining these regulatory networks have focused on derivatives of the strain NCTC 8325, most notably RN6390. However, all NCTC 8325 derivatives, including RN6390, possess an 11 bp deletion in rsbU. This deletion renders NCTC 8325 derivatives naturally sigma-factor-B deficient. Recent studies have shown that RN6390 is also deficient, in comparison to clinical isolates, with respect to biofilm formation, a process which is important for both pathogenesis and antimicrobial resistance. Based on these considerations, the authors carried out genome-scale transcriptional profiling, comparing RN6390 with the virulent rsbU-positive clinical isolate UAMS-1. The results revealed significant genome-wide differences in expression patterns between RN6390 and UAMS-1, and suggested that the overall transcriptional profile of UAMS-1 is geared toward expression of factors that promote colonization and biofilm formation. In contrast, the transcriptional profile of RN6390 was heavily influenced by RNAIII expression, resulting in a phenotype characterized by increased production of exoproteins, and decreased capacity to form a biofilm. The greater influence of agr in RN6390 relative to UAMS-1 was also evident when the transcriptional profile of UAMS-1 was compared with that of its isogenic sarA and agr mutants. Specifically, the results indicate that, in contrast to NCTC 8325 derivatives, agr plays a limited role in overall regulation of gene expression in UAMS-1, when compared with sarA. Furthermore, by defining the sarA regulon in a biofilm-positive clinical isolate, and comparing the results with transcriptional profiling experiments defining biofilm-associated gene expression patterns in the same strain, the authors identified a sarA-regulated operon (alsSD) that is also induced in biofilms, and demonstrated that mutation of alsSD results in reduced capacity to form a biofilm.

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Activity ofStaphylococcus epidermidisPhenol‐Soluble Modulin Peptides Expressed inStaphylococcus carnosus

Cited by 32 publications

References 24 publications

The AgrD N-Terminal Leader Peptide of Staphylococcus aureus Has Cytolytic and Amyloidogenic Properties

The AgrD N-Terminal Leader Peptide of Staphylococcus aureus Has Cytolytic and Amyloidogenic Properties

The Virulence Regulator Agr Controls the Staphylococcal Capacity to Activate Human Neutrophils via the Formyl Peptide Receptor 2

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

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