Utilizing Chemical Biology Approaches to Study Streptococcal Quorum Sensing
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Authors
Brennan, Alec
Issue Date
2025
Type
Dissertation
Language
en_US
Keywords
Biotherapeutic potential , Competence regulon , Peptide , Quorum sensing , Streptococci
Alternative Title
Abstract
Bacteria have proven to be vital to the global ecosystem and our everyday lives, as they largely influence the delicate balance between health and disease. Of particular interest are Gram-positive bacteria known as streptococci, as these bacteria are incredibly common throughout the human microbiota. Many streptococci are considered commensals that contribute to beneficial health effects; however, some are also considered opportunistic pathogens, possessing natural competence for genetic transformation and the improved ability to acquire antimicrobial resistance. While it may seem logical to simply develop new antibiotics to treat infection, it is incredibly time-consuming, fiscally demanding, and difficult to discover novel antibiotic classes and develop new antibiotic derivatives. Moreover, the advent of antibiotic derivatives is closely followed by the emergence and spread of bacterial resistance, so continually developing new antibiotics has become ineffective. The impracticality of developing new antibiotic classes, coupled with the increased prominence of bacterial resistance demands the development of novel therapeutics that avoid selecting for antibiotic resistance amongst these bacteria. One such method is utilizing chemical biology tools to target nonessential pathways to hinder bacterial proliferation and pathogenesis. Here, the investigation of a cell-to-cell signaling mechanism known as quorum sensing (QS) is explored to further elucidate mechanisms to address and treat bacterial infection without selecting for antibiotic resistance. Generally, streptococci coordinate group behaviors and downstream phenotypes via the competence stimulating peptide (CSP)-mediated QS pathway known as the comABCDE regulon. Once exogenous CSP reaches a critical concentration threshold, bacterial populations are capable of acting synchronously to engage in specific, advantageous behaviors and phenotypes. This study aims to explore this pathway to gain insights about downstream phenotypic expression profiles, such as competence, biofilm formation, virulence factor production, and peroxide formation.
To this end, the competence regulon and downstream phenotypic expression profiles have been investigated in three species: Streptococcus sinensis, Streptococcus cristatus, and Streptococcus gordonii. In Chapter II, the role of the competence regulon in the pathogenesis of S. sinensis, an emerging human pathogen, was explored, with specific attention to transcriptomic and phenotypic effects following CSP exposure. In Chapters III and IV, the possibility of utilizing the competence regulon to enhance the biotherapeutic potential of two oral commensals, S. cristatus and S. gordonii, respectively, was investigated. Both species had previously demonstrated the ability to generate inhibitory hydrogen peroxide against a notorious oral pathogen, Streptococcus mutans, however studies here aimed to understand the connection between this phenotype and the competence regulon. Overall, this work largely explores the use of chemical biology tools to study streptococcal QS with the aim of providing foundational knowledge for future biotherapeutic approaches.