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Expanding Our Arsenal against Streptococcus pneumoniae Infections: Disrupting Pneumococcus Communication by Modulating the Competence Quorum Sensing System
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Streptococcus pneumoniae is a major pathogen that utilizes quorum sensing (QS), the ability of bacteria to coordinate gene expression in a population-dependent manner, to regulate genetic transformation, virulence and biofilm formation, all of which are critical to the pathogenicity of the bacteria. Therefore, targeting QS could potentially lead to the design of alternative therapies to treat pneumococcal infections. A key step in the activation of the pneumococcal QS circuitry is the interaction between the competence stimulating peptide (CSP) and its receptor ComD. There are two major subtypes of CSP, namely CSP1 and CSP2, which bind their cognate receptor, ComD1 and ComD2, respectively. My projects aim to develop synthetic CSP-based analogues capable of modulating pneumococcal QS by intercepting the CSP:ComD interaction. I have conducted a systematic structure-function relationship (SAR) analysis of CSP1 and identified several key residues that are critical to receptor binding, activation, and specificity. Additionally, I used CD spectroscopy to assess the global structural features of CSP1 and analogues, and observed a strong correlation between helicity and bioactivity. Moreover, my 2D-NMR studies on CSP1 and several analogues revealed two distinct hydrophobic patches that are required for effective ComD1 and ComD2 binding. I also performed an SAR study on the N-terminus of CSP1, which revealed more structural features that are important to receptor binding and activation.