Abstract
Bacterial infections continue to threaten humankind and the rapid spread of antibiotic resistant bacteria is alarming. Current antibiotics target essential bacterial processes and thereby apply a strong selective pressure on pathogenic and non-pathogenic bacteria alike. One alternative strategy is to block bacterial virulence systems that are essential for the ability to cause disease but not for general bacterial viability. We have previously show that the plant natural product (-)-hopeaphenol blocks the type III secretion system (T3SS) in the Gram-negative pathogens Yersinia pseudotuberculosis and Pseudomonas aeruginosa. (-)-Hopeaphenol is a resveratrol tetramer and in the present study we explore various resveratrol dimers, including partial structures of (-)-hopeaphenol, as T3SS inhibitors. To allow rapid and efficient assessment of T3SS inhibition in P. aeruginosa, we developed a new screening method by using a green fluorescent protein reporter under the control of the ExoS promoter. Using a panel of assays we showed that compounds with a benzofuran core structure i.e. viniferifuran, dehydroampelopsin B, anigopreissin A, dehydro-δ-viniferin and resveratrol-piceatannol hybrid displayed significant to moderate activities towards the T3SS in Y. pseudotuberculosis and P. aeruginosa.
Highlights
The discovery and introduction of antibiotics is recognized as one of the greatest advances in therapeutic medicine during the 20th century
We investigated the biological effects of selected natural benzofuran resveratrol dimers and analogues on the T3SS in comparison to (-)-hopeaphenol
The fact that the inhibition profile of the resveratrol tetramer (-)-hopeaphenol is maintained by the resveratrol dimer viniferifuran is encouraging since it has a simplified structure that can be prepared in gram quantities in only four steps[11]
Summary
The discovery and introduction of antibiotics is recognized as one of the greatest advances in therapeutic medicine during the 20th century. One strategy is to develop therapeutic agents that act on major virulence systems in pathogenic bacteria and disarm them and assist the immune defense in clearing the pathogen. Virulence blocking agents are expected to act on bacterial strains resistant to conventional antibiotics in current use. Acquired resistance results from horizontal gene transfer and mutations leading to reduced uptake, efflux pump overexpression, target mutations, and expression of antibiotic modifying enzymes such as extended-spectrum β-lactamases. Adaptive resistance is the result of triggering factors such as antibiotics, biocides, polyamines, pH, anaerobiosis, cations, and carbon sources, as well as social behavior in biofilm formation and swarming These factors modulate expression of genes that lead to increased resistance. Fluorescence microscopy was subsequently used to show the interaction of the T3SS inhibitor viniferifuran with bacterial cells
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