Triterpenoid acids isolated from Schinus terebinthifolia fruits reduce Staphylococcus aureus virulence and abate dermonecrosis

Huaqiao Tang,Huaqiao Tang,Gina Porras,Morgan M Brown,Francois Chassagne,John Bacsa,Cassandra L Quave,James T Lyles,Alexander R Horswill

doi:10.1038/s41598-020-65080-3

Huaqiao Tang, Huaqiao Tang + Show 7 more

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https://doi.org/10.1038/s41598-020-65080-3

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Abstract

Staphylococcus aureus relies on quorum sensing to exert virulence to establish and maintain infection. Prior research demonstrated the potent quorum sensing inhibition effects of “430D-F5”, a refined extract derived from the fruits of Schinus terebinthifolia, a medicinal plant used for the traditional treatment of skin and soft tissue infections. We report the isolation and identification of three compounds from 430D-F5 that reduce virulence and abate dermonecrosis: 3-oxo-olean-12-en-28-oic acid (1), 3-oxotirucalla-7,24Z-dien-26-oic acid (2) and 3α-hydroxytirucalla-7,24 Z-dien-27-oic acid (3). Each compound inhibits all S. aureus accessory gene regulator (agr) alleles (IC50 2–70 μM). Dose-dependent responses were also observed in agr-regulated reporters for leucocidin A (lukA, IC50 0.4-25 μM) and glycerol ester hydrolase or lipase (gehB, IC50 1.5–25 μM). Surprisingly, dose-dependent activity against the nuclease reporter (nuc), which is under the control of the sae two-component system, was also observed (IC50 0.4–12.5 μM). Compounds 1-3 exhibited little to no effect on the agr-independent mgrA P2 reporter (a constitutive promoter from the mgrA two-component system) and the esxA reporter (under control of mgrA). Compounds 1-3 inhibited δ-toxin production in vitro and reduced dermonecrosis in a murine in vivo model. This is the first report of triterpenoid acids with potent anti-virulence effects against S. aureus.

Highlights

Staphylococcus aureus relies on quorum sensing to exert virulence to establish and maintain infection
Prior research demonstrated the potent quorum sensing inhibition effects of “430D-F5”, a refined extract derived from the fruits of Schinus terebinthifolia, a medicinal plant used for the traditional treatment of skin and soft tissue infections
Interference with bacterial virulence has emerged as an attractive approach among the current strategies for developing new anti-infective drugs

Summary

Introduction

Staphylococcus aureus relies on quorum sensing to exert virulence to establish and maintain infection. Each compound inhibits all S. aureus accessory gene regulator (agr) alleles (IC50 2–70 μM). Compounds 1-3 inhibited δ-toxin production in vitro and reduced dermonecrosis in a murine in vivo model This is the first report of triterpenoid acids with potent antivirulence effects against S. aureus. S. aureus uses multiple two-component systems to sense and respond to changes in cell density and environmental cues One of these two-component systems is the Accessory Gene Regulator (agr) system, which has been extensively characterized for its complex regulatory role in global MRSA virulence and its requirement for MRSA skin infection pathogenesis. Agr senses and responds to its cognate auto-inducing peptide (AIP) signal in a cell-density dependent manner. As the primary effector of the agr system, RNAIII post-transcriptionally regulates the expression of more than 200 virulence-associated genes including toxins (α, β, δ, and γ), proteases, lipases, superantigens (toxic shock syndrome toxin-1, enterotoxins B, C, and D), and leukocidins. The RNAIII transcript includes the hld gene for δ-toxin, an amphipathic 26 amino acid peptide with cytolytic activity

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