Abstract
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.
Highlights
Staphylococcus aureus is a serious human bacterial pathogen that causes infections ranging from minor skin and soft tissue infections to osteomyelitis, sepsis and necrotizing pneumonia [1]
In the early 1990’s highly invasive community-associated methicillin resistant S. aureus (CA-MRSA) strains emerged such as USA300 [2,3]
Our results show that norlichexanthone reduces virulence gene expression in the CA-MRSA strain USA300 and that it modulates virulence gene expression by interfering with at least two different key virulence gene regulons; the agr and the SaeRS two component systems
Summary
Staphylococcus aureus is a serious human bacterial pathogen that causes infections ranging from minor skin and soft tissue infections to osteomyelitis, sepsis and necrotizing pneumonia [1]. In the early 1990’s highly invasive community-associated methicillin resistant S. aureus (CA-MRSA) strains emerged such as USA300 [2,3]. This strain has become one of the predominant CA-MRSA clones and it is evolving towards resistance against several antibiotic classes [4]. In S. aureus, the agr quorum sensing system controls expression of numerous virulence factors in response to cell density, including α-hemolysin and the phenol-soluble modulins (PSMs), that contribute to the virulence of CA-MRSA [7]. Other two-component systems 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 [10,11,12]. Both agr and SaeRS influence biofilm formation in S. aureus, with agr acting through production of the PSMs [13] and SaeRS by repressing production of extracellular proteases degrading proteins of importance to biofilm formation [14]
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