Virulence Inhibitors from Brazilian Peppertree Block Quorum Sensing and Abate Dermonecrosis in Skin Infection Models

Sci Rep. 2017 Feb 10;7:42275. doi: 10.1038/srep42275.

Abstract

Widespread antibiotic resistance is on the rise and current therapies are becoming increasingly limited in both scope and efficacy. Methicillin-resistant Staphylococcus aureus (MRSA) represents a major contributor to this trend. Quorum sensing controlled virulence factors include secreted toxins responsible for extensive damage to host tissues and evasion of the immune system response; they are major contributors to morbidity and mortality. Investigation of botanical folk medicines for wounds and infections led us to study Schinus terebinthifolia (Brazilian Peppertree) as a potential source of virulence inhibitors. Here, we report the inhibitory activity of a flavone rich extract "430D-F5" against all S. aureus accessory gene regulator (agr) alleles in the absence of growth inhibition. Evidence for this activity is supported by its agr-quenching activity (IC50 2-32 μg mL-1) in transcriptional reporters, direct protein outputs (α-hemolysin and δ-toxin), and an in vivo skin challenge model. Importantly, 430D-F5 was well tolerated by human keratinocytes in cell culture and mouse skin in vivo; it also demonstrated significant reduction in dermonecrosis following skin challenge with a virulent strain of MRSA. This study provides an explanation for the anti-infective activity of peppertree remedies and yields insight into the potential utility of non-biocide virulence inhibitors in treating skin infections.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Anacardiaceae / chemistry*
  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Biofilms / drug effects
  • Disease Models, Animal
  • Hemolysin Proteins / pharmacology
  • Humans
  • Methicillin-Resistant Staphylococcus aureus / drug effects
  • Mice
  • Microbial Sensitivity Tests
  • Microbiota
  • Necrosis
  • Plant Extracts / chemistry
  • Plant Extracts / isolation & purification
  • Plant Extracts / toxicity
  • Quorum Sensing* / drug effects
  • Skin / drug effects
  • Skin / microbiology
  • Skin / pathology
  • Skin Diseases / microbiology
  • Skin Diseases / pathology*
  • Soft Tissue Infections / microbiology
  • Soft Tissue Infections / pathology
  • Toxins, Biological / chemistry
  • Toxins, Biological / toxicity
  • Virulence / drug effects

Substances

  • Anti-Bacterial Agents
  • Hemolysin Proteins
  • Plant Extracts
  • Toxins, Biological