Quorum sensing, a cell-density dependent form of bacterial communication used by the notorious human pathogen Streptococcus pneumoniae, can result in the bacteria’s ability to resist antibiotics, increased virulence, and increased pathogenic properties. S. pneumoniae utilizes its quorum sensing circuitry and associated signaling peptide, the Competence Stimulating Peptide (CSP), to regulate such properties. Strains of S. pneumoniae can be split into two different specificity groups based on their CSP signal produced. These two variants are CSP1 and CSP2; where CSP1 is the focus of this study. Through the modification of the six hydrophobic amino acid residues that comprise the quorum-sensing signaling peptide, a series more competitive, synthetic peptides were created to modulate quorum sensing in S.pneumoniae. From previous research, the substitution of alanine for glutamic acid at the N-terminus of the peptide eliminates activation at the ComD1 site, resulting in a conversion to a ComD1 inhibitor. Using this E1A substitution, and our peptides containing hydrophobic modifications made from previously successful peptides that exhibited high receptor activation, a library of inhibitory CSP1 peptides was created. It was hypothesized that increasing the binding efficiency in the peptide in combination with the E1A substitution could produce a peptide to out-compete the natural CSP1, resulting in blocking the bacteria’s ability to initiate quorum sensing. Multiple notable ComD1 inhibitors were discovered including E1AL4NVI12NL, E1AI12NL, E1AL4NV, and E1AI2L. The E1AL4NVI12NL peptide was found to be the most potent ComD1 inhibitor to date, holding an IC50 value of 54.58 nM. These results reveal important information about the structure of CSP1 and how it works as a ComD1 inhibitor in relation to the optimized hydrophobic residues.

Quorum sensing inhibition in Streptococcus pneumoniae using optimized CSP1 modifications including a key E1A substitution

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.