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A Fluorescence-based Method to Study Bacterial Gene Regulation in Infected Tissues
Published on: February 19, 2019
Norlichexanthone Reduces Virulence Gene Expression and Biofilm Formation in Staphylococcus aureus
Mara Baldry1, Anita Nielsen1, Martin S Bojer1
1Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark.
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.
Insights
Norlichexanthone, an anti-virulence compound, reduces Staphylococcus aureus toxicity by inhibiting AgrA binding and biofilm formation. This discovery offers a new strategy against antibiotic-resistant MRSA strains.
Area of Science:
- Microbiology
- Pharmacology
- Molecular Biology
Background:
- Staphylococcus aureus, particularly methicillin-resistant strains (MRSA) like USA300, poses a significant threat due to antibiotic resistance.
- Anti-virulence therapy, targeting toxicity rather than bacterial viability, is a promising strategy to combat resistance.
- Norlichexanthone, a fungal polyketide, previously showed potential in reducing virulence factor expression in S. aureus.
Purpose of the Study:
- To further characterize the mechanism of action of norlichexanthone.
- To investigate its effect on virulence factor expression and biofilm formation in community-associated MRSA (CA-MRSA) strain USA300.
- To explore its impact on the AgrA and SaeRS regulatory systems.
Main Methods:
- Investigated norlichexanthone's effect on alpha-hemolysin (hla) and RNAIII expression in S. aureus USA300.
- Assessed norlichexanthone's impact on S. aureus toxicity towards human neutrophils.
- Performed transcriptomic analysis to identify regulated genes and pathways.
- Examined norlichexanthone's direct interaction with the AgrA DNA binding target.
- Evaluated norlichexanthone's effect on biofilm formation.
Main Results:
- Norlichexanthone reduced hla and RNAIII expression in S. aureus USA300, similar to its effect in strain 8325-4.
- It decreased S. aureus toxicity to human neutrophils and directly interfered with AgrA binding to its DNA target.
- Unlike ω-hydroxyemodin, norlichexanthone inhibited S. aureus biofilm formation.
- Transcriptomic data indicated repression of SaeRS-regulated genes by norlichexanthone.
Conclusions:
- Norlichexanthone effectively reduces key virulence factor expression in CA-MRSA USA300 by inhibiting AgrA binding.
- It also represses biofilm formation, presenting a dual-action anti-virulence mechanism.
- Norlichexanthone represents a potential therapeutic agent against antibiotic-resistant S. aureus infections.
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