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Elucidating the Role of Quorum Sensing (QS) and Developing QS Modulators for Streptococcus pneumoniae and Its Close Commensal Relative, Streptococcus mitis
AuthorMilly, Tahmina Ahmed
AdvisorTal-Gan, Yftah YT
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Quorum sensing (QS) is a ubiquitous communication mechanism in bacteria that controls bacterial group behavior phenotypes, such as competence, biofilm formation, and virulence factor production. Streptococcus pneumoniae, an opportunistic pathogen, and Streptococcus mitis are prototypes of commensal bacteria in the Mitis group and share >80% of their genes. Both S. mitis and S. pneumoniae utilize a peptide pheromone (competence stimulating peptide, CSP), which binds to its membrane bound ComD receptor to induce QS responses and different pathogenic phenotypes. The aim of this study was to target this non- essential bacterial communication pathway through impediment of the peptide-receptor interaction by using synthetic CSP analogs, thereby circumventing a key issue with traditional antibiotics, the introduction of selective pressure for resistance development. To this end, I have conducted comprehensive structure-activity relationship (SAR) analyses of both S. pneumoniae and S. mitis CSPs to gain a deeper understanding of the molecular mechanisms that drive these QS circuitries. The SAR results revealed several interesting activity trends and uncovered several CSP-based QS modulators with distinct activity profiles. Additionally, I evaluated several phenotypes that can be utilized to assess the effect of lead peptide analogs on the expression of group behavior genes. In addition to yielding a series of new QS activators and inhibitors, key SAR knowledge of the CSP pheromones obtained through this study, can be utilized for the rational design of highly potent, pharmacologically stable CSP-based QS modulators with therapeutic potential.