Sustained Release of a Synthetic Autoinducing Peptide Mimetic Blocks Bacterial Communication and Virulence In Vivo

There is significant interest in approaches to the treatment of bacterial infections that block virulence without creating selective pressures that lead to resistance. Here, we report the development of an “anti‐virulence” strategy that exploits the activity of potent synthetic inhibitors of quorum...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2022-06, Vol.61 (24), p.e202201798-n/a
Main Authors: West, Korbin H. J., Gahan, Curran G., Kierski, Patricia R., Calderon, Diego F., Zhao, Ke, Czuprynski, Charles J., McAnulty, Jonathan F., Lynn, David M., Blackwell, Helen E.
Format: Article
Language:English
Subjects:
Anti-Infective
Bacteria
Bacterial diseases
Bacterial infections
Cell–Cell Signalling
Chemical communication
Controlled Release
Drug resistance
Infections
Inhibitors
Methicillin
Microparticles
Peptides
Polymers
Quorum Sensing
Skin
Skin resistance
Staphylococcus aureus
Sustained release
Virulence
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:There is significant interest in approaches to the treatment of bacterial infections that block virulence without creating selective pressures that lead to resistance. Here, we report the development of an “anti‐virulence” strategy that exploits the activity of potent synthetic inhibitors of quorum sensing (QS) in Staphylococcus aureus. We identify peptide‐based inhibitors of QS that are resistant to sequestration or degradation by components of murine tissue and demonstrate that encapsulation of a lead inhibitor in degradable polymer microparticles provides materials that substantially inhibit QS in vitro. Using a murine abscess model, we show that this inhibitor attenuates methicillin‐resistant S. aureus (MRSA) skin infections in vivo, and that sustained release of the inhibitor from microparticles significantly improved outcomes compared to mice that received a single‐dose bolus. Our results present an effective and modular approach to controlling bacterial virulence in vivo and could advance the development of new strategies for skin infection control. A synthetic peptide was found to block cell‐to‐cell signalling, or quorum sensing, in bacteria and be highly bioavailable in mouse tissue. The controlled release of this agent from degradable polymeric microparticles strongly inhibited skin infection in a wound model at levels that far surpassed the potency of the peptide when delivered conventionally.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202201798