The effect of skin fatty acids on Staphylococcus aureus

Neumann, Yvonne; Ohlsen, Knut; Donat, Stefanie; Engelmann, Susanne; Kusch, Harald; Albrecht, Dirk; Cartron, Michaël L.; Hurd, Alexander F.; Foster, Simon J.

doi:10.1007/s00203-014-1048-1

Cited by 32 publications

(43 citation statements)

References 85 publications

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“…Instead, the presence of oleic acid led to the downregulation of SaeRS-mediated genes in both wild-type and vfrB mutant strains. This finding is not unlike a previous observation that the major human skin fatty acid, cis-6-hexadecenoic acid, downregulated genes of the SaeRS regulon in S. aureus SH1000, through an undefined mechanism (49). Furthermore, we found that the addition of a saturated fatty acid (myristic acid) did not induce the transcription of coa in wild-type or vfrB mutant strains.…”

Section: Discussioncontrasting

confidence: 99%

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

2017

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In previous studies, we identified the fatty acid kinase virulence factor regulator B (VfrB) as a potent regulator of ␣-hemolysin and other virulence factors in Staphylococcus aureus. In this study, we demonstrated that VfrB is a positive activator of the SaeRS two-component regulatory system. Analysis of vfrB, saeR, and saeS mutant strains revealed that VfrB functions in the same pathway as SaeRS. At the transcriptional level, the promoter activities of SaeRS class I (coa) and class II (hla) target genes were downregulated during the exponential growth phase in the vfrB mutant, compared to the wild-type strain. In addition, saePQRS expression was decreased in the vfrB mutant strain, demonstrating a need for this protein in the autoregulation of SaeRS. The requirement for VfrB-mediated activation was circumvented when SaeS was constitutively active due to an SaeS (L18P) substitution. Furthermore, activation of SaeS via human neutrophil peptide 1 (HNP-1) overcame the dependence on VfrB for transcription from class I Sae promoters. Consistent with the role of VfrB in fatty acid metabolism, hla expression was decreased in the vfrB mutant with the addition of exogenous myristic acid. Lastly, we determined that aspartic acid residues D38 and D40, which are predicted to be key to VfrB enzymatic activity, were required for VfrB-mediated ␣-hemolysin production. Collectively, this study implicates VfrB as a novel accessory protein needed for the activation of SaeRS in S. aureus.IMPORTANCE The SaeRS two-component system is a key regulator of virulence determinant production in Staphylococcus aureus. Although the regulon of this twocomponent system is well characterized, the activation mechanisms, including the specific signaling molecules, remain elusive. Elucidating the complex regulatory circuit of SaeRS regulation is important for understanding how the system contributes to disease causation by this pathogen. To this end, we have identified the fatty acid kinase VfrB as a positive regulatory modulator of SaeRS-mediated transcription of virulence factors in S. aureus. In addition to describing a new regulatory aspect of SaeRS, this study establishes a link between fatty acid kinase activity and virulence factor regulation.

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Section: Discussioncontrasting

confidence: 99%

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

2017

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“…The human skin fatty acid cis -6-hexadecenoic acid was reported to repress the Sae system, although the mechanism is not known [52]. 18β-glycyrrhetinic acid, a component of the licorice root Glycyrrhiza spp., was also shown to inhibit the transcription of saeR and hla , raising the possibility that it might specifically repress the Sae system.…”

Section: Signalsmentioning

confidence: 99%

The SaeRS Two‐Component System of Staphylococcus aureus

Liu

Yeo

Bae

2016

Genes

178

195

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In the Gram-positive pathogenic bacterium Staphylococcus aureus, the SaeRS two-component system (TCS) plays a major role in controlling the production of over 20 virulence factors including hemolysins, leukocidins, superantigens, surface proteins, and proteases. The SaeRS TCS is composed of the sensor histidine kinase SaeS, response regulator SaeR, and two auxiliary proteins SaeP and SaeQ. Since its discovery in 1994, the sae locus has been studied extensively, and its contributions to staphylococcal virulence and pathogenesis have been well documented and understood; however, the molecular mechanism by which the SaeRS TCS receives and processes cognate signals is not. In this article, therefore, we review the literature focusing on the signaling mechanism and its interaction with other global regulators.

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“…AgrA controls expression of the divergently transcribed RNAIII expressed from the P3 promoter as well as of the PSMs [8,9]. Other two-component systems also modulate virulence including the auto-regulated SaeRS that responds to external stimuli such as pH, NaCl, sub-inhibitory concentrations of antimicrobial peptides and human skin fatty acids [10–12]. In addition to virulence, both agr and SaeRS influence biofilm formation in S .…”

Section: Introductionmentioning

confidence: 99%

Norlichexanthone Reduces Virulence Gene Expression and Biofilm Formation in Staphylococcus aureus

et al. 2016

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Staphylococcus aureus is a serious human pathogen and antibiotic resistant, community-associated strains, such as the methicillin resistant S. aureus (MRSA) strain USA300, continue to spread. To avoid resistance, anti-virulence therapy has been proposed where toxicity is targeted rather than viability. Previously we have shown that norlichexanthone, a small non-reduced tricyclic polyketide produced by fungi and lichens, reduces expression of hla encoding α-hemolysin as well as the regulatory RNAIII of the agr quorum sensing system in S. aureus 8325–4. The aim of the present study was to further characterise the mode of action of norlichexanthone and its effect on biofilm formation. We find that norlichexanthone reduces expression of both hla and RNAIII also in strain USA300. Structurally, norlichexanthone resembles ω-hydroxyemodin that recently was shown to bind the agr two component response regulator, AgrA, which controls expression of RNAIII and the phenol soluble modulins responsible for human neutrophil killing. We show that norlichexanthone reduces S. aureus toxicity towards human neutrophils and interferes directly with AgrA binding to its DNA target. In contrast to ω-hydroxyemodin however, norlichexanthone reduces staphylococcal biofilm formation. Transcriptomic analysis revealed that genes regulated by the SaeRS two-component system are repressed by norlichexanthone when compared to untreated cells, an effect that was mitigated in strain Newman carrying a partially constitutive SaeRS system. Our data show that norlichexanthone treatment reduces expression of key virulence factors in CA-MRSA strain USA300 via AgrA binding and represses biofilm formation.

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The effect of skin fatty acids on Staphylococcus aureus

Cited by 32 publications

References 85 publications

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

VfrB Is a Key Activator of the Staphylococcus aureus SaeRS Two-Component System

The SaeRS Two‐Component System of Staphylococcus aureus

Norlichexanthone Reduces Virulence Gene Expression and Biofilm Formation in Staphylococcus aureus

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