Norlichexanthone Reduces Virulence Gene Expression and Biofilm Formation in Staphylococcus aureus

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.

Chitosan-propolis nanoparticle formulation demonstrates anti-bacterial activity against Enterococcus faecalis biofilms

“…Genes involved in adhesion and antibiotic resistances were found to be overexpressed in biofilm bacteria [65] as observed in our system. Treatment with anti-bacterial agents is reported to be capable of reducing virulence gene expression [66] corroborating our findings.…”

Herring Oil and Omega Fatty Acids Inhibit Staphylococcus aureus Biofilm Formation and Virulence

“…α-Hemolysin is known to play a critical role in cell-to-cell interactions during biofilm formation ( Caiazza and O’Toole, 2003 ; Anderson et al, 2012 ; Scherr et al, 2015 ). This reduction of α-hemolysin expression has been discovered in recently published articles showing that alizarin ( Lee et al, 2016 ), azithromycin ( Gui et al, 2014 ), flavonoids ( Cho et al, 2015 ), norlichexanthone ( Baldry et al, 2016 ), and stilbenoids ( Lee et al, 2014 ) inhibit both biofilm formation and hemolysis by S. aureus . Our findings support that α-hemolysin has a positive relationship with biofilm formation in S. aureus .…”

A Novel Antimicrobial Coating Represses Biofilm and Virulence-Related Genes in Methicillin-Resistant Staphylococcus aureus

“…The two component systems, AgrCA and SaeRS influence biofilm formation in S. aureus , by the production of PSMs and by suppressing the synthesis of extracellular proteases, respectively ( Baldry et al, 2016 ). The extracellular proteases degrade proteins that are important for biofilm formation ( Baldry et al, 2016 ).…”

“…The two component systems, AgrCA and SaeRS influence biofilm formation in S. aureus , by the production of PSMs and by suppressing the synthesis of extracellular proteases, respectively ( Baldry et al, 2016 ). The extracellular proteases degrade proteins that are important for biofilm formation ( Baldry et al, 2016 ). In S. aureus , the saeRS system regulates the production of many virulence factors such as leukocidins, superantigens, proteases, surface proteins, and hemolysins ( Liu et al, 2016 ).…”