Development and Structural Analysis of Peptide-Based Probes for Modulating Quorum Sensing in Streptococcal Bacteria
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Authors
Mehrani, Mona
Issue Date
2025
Type
Dissertation
Language
en_US
Keywords
Alternative Title
Abstract
The growing challenge of antibiotic resistance has complicated bacterial infection treatment, emphasizing the need for alternative therapies that circumvent selective pressure. Modulating quorum sensing (QS) with peptide analogs is a promising non-bacteriocidal alternative approach to mitigate bacterial pathogenicity and resistance development. In pursuit of novel therapeutics, this study explored peptide-based treatments to understand how peptide signals modulate QS in two distinct streptococcal species, Streptococcus pneumoniae and Streptococcus constellatus. Furthermore, we conducted a structural analysis of these peptides to provide insights into the design of more stable and potent analogs. The second chapter focuses on the structural and functional optimization of cyclic peptide analogs built upon the S. pneumoniae CSP1-E1A scaffold. Using urea bridge chemistry, libraries of peptides with varying ring sizes and bridge positions were synthesized to pinpoint the optimal region for cyclization. This study also examined how different parameters such as ring size and bridge position influence the overall peptide conformation, with a specific focus on α-helicity, and evaluated their biological activity against S. pneumoniae.
In the third chapter, we identified the competence-stimulating peptide (CSP) of S. constellatus and explored how its competence regulon influences two major phenotypic traits: competence and biofilm development. Moreover, through a comprehensive structure-activity relationship analysis, we determined key structural motifs required for effective ComD receptor binding and activation. We also examined the secondary structure of mutated CSP analogs to investigate the correlation between peptide secondary structure and QS activation. Overall, this study advances our understanding of QS in streptococcal species and paves the way for the development of CSP-based modulators, which could lead to the advancement of novel peptide-based therapies for future medical use.