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Download fileStructure Activity Relationship Study of the XIP Quorum Sensing Pheromone in Streptococcus mutans Reveal Inhibitors of the Competence Regulon
journal contribution
posted on 2020-10-02, 14:23 authored by Chowdhury
Raihan Bikash, Yftah Tal-GanThe
dental cariogenic pathogen Streptococcus mutans coordinates
competence for genetic transformation via two peptide
pheromones, competence stimulating peptide (CSP) and comX-inducing peptide (XIP). CSP is sensed by the comCDE system and induces
competence indirectly, whereas XIP is sensed by the comRS system and
induces competence directly. In chemically defined media (CDM), after
uptake by oligopeptide permease, XIP interacts with the cytosolic
receptor ComR to form the XIP::ComR complex that activates the expression
of comX, an alternative sigma factor that initiates
the transcription of late-competence genes. In this study, we set
out to determine the molecular mechanism of XIP::ComR interaction.
To this end, we performed systematic replacement of the amino acid
residues in the XIP pheromone and assessed the ability of the mutated
analogs to modulate the competence regulon in CDM. We were able to
identify structural features that are important to ComR binding and
activation. Our structure–activity relationship insights led
us to construct multiple XIP-based inhibitors of the comRS pathway.
Furthermore, when comCDE and comRS were both stimulated with CSP and
XIP, respectively, a lead XIP-based inhibitor was able to maintain
the inhibitory activity. Last, phenotypic assays were used to highlight
the potential of XIP-based inhibitors to attenuate pathogenicity in S. mutans and to validate the specificity of these compounds
to the comRS pathway within the competence regulon. The XIP-based
inhibitors developed in this study can be used as lead scaffolds for
the design and development of potential therapeutics against S. mutans infections.