Related Experiment Video
Updated: Aug 22, 2025
Construction of Cyclic Cell-Penetrating Peptides for Enhanced Penetration of Biological Barriers
Published on: September 19, 2022
Peptoid-Peptide Hybrid Analogs of the Enterococcus faecalis Fsr Auto-Inducing Peptide (AIP) Reveal Crucial
Dominic N McBrayer1, Uttam Ghosh1, Muralikrishna Lella1
1Department of Chemistry, University of Nevada, Reno, 1664 N. Virginia Street, Reno, NV-89557, USA.
Abstract:
As multidrug-resistant bacteria become a more pressing risk to human health, alternate approaches to treating bacterial infections are being increasingly investigated. Enterococcus faecalis is an opportunistic pathogen responsible for a large percentage of secondary enterococci infections. Its pathogenicity has been shown to be largely dependent on a cell-density communication mechanism, termed quorum sensing. In this study, we conducted a systematic investigation of the lactone-containing macrocyclic signaling peptide used by E. faecalis for Fsr-mediated communication, termed gelatinase biosynthesis activating pheromone (GBAP). Specifically, through a combination of the on-resin sub-monomer and solution phase peptoid building block synthesis approaches, we successfully synthesized a library of peptoid-peptide hybrid analogs of GBAP and determined the biological effects associated with the introduction of the peptoid (N-alkyl glycine derivative) modifications. Within the macrocycle region of the peptide, as have been seen with other modifications, the F7 site was unusually tolerant toward peptoid modification, compared with other macrocyclic sites. Interestingly, within the exocyclic tail, peptoid modification at the N2 site completely abolished activity, a first for a single tail modification.
Insights
Researchers explored modifications to gelatinase biosynthesis activating pheromone (GBAP), a key communication molecule in Enterococcus faecalis. Peptoid changes in the tail region abolished activity, offering new insights into bacterial signaling and potential therapeutic targets.
Area of Science:
- Microbiology
- Synthetic Chemistry
- Drug Discovery
Background:
- Multidrug-resistant bacteria pose a significant threat to public health, necessitating novel treatment strategies.
- Enterococcus faecalis is an opportunistic pathogen contributing to secondary infections, with its virulence linked to quorum sensing.
- Quorum sensing in E. faecalis relies on signaling molecules like gelatinase biosynthesis activating pheromone (GBAP).
Purpose of the Study:
- To systematically investigate the structure-activity relationship of GBAP by synthesizing peptoid-peptide hybrid analogs.
- To determine the impact of peptoid modifications on the biological activity of GBAP in E. faecalis communication.
- To identify potential sites for modification that could modulate bacterial signaling pathways.
Main Methods:
- Synthesis of a library of peptoid-peptide hybrid analogs of GBAP using on-resin sub-monomer and solution phase approaches.
- Biological evaluation of synthesized analogs to assess their effects on Fsr-mediated communication.
- Comparative analysis of peptoid modifications at different sites within the GBAP structure.
Main Results:
- The F7 site within the macrocycle region showed tolerance to peptoid modification, similar to other observed modifications.
- Peptoid modification at the N2 site of the exocyclic tail completely abolished GBAP activity, a novel finding for a single tail modification.
- The study successfully generated diverse GBAP analogs with varying biological activities.
Conclusions:
- Peptoid modifications can significantly alter the function of bacterial signaling peptides like GBAP.
- The N2 site in the exocyclic tail of GBAP is critical for its activity, representing a potential target for antimicrobial strategies.
- Understanding these structure-activity relationships can inform the development of new approaches to combat bacterial infections.
More Related Videos
10:59Enrichment of Bacterial Lipoproteins and Preparation of N-terminal Lipopeptides for Structural Determination by Mass Spectrometry
Published on: May 21, 2018
13:42Solid-phase Submonomer Synthesis of Peptoid Polymers and their Self-Assembly into Highly-Ordered Nanosheets
Published on: November 2, 2011
