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ACS Chem Biol

Title:		Structure Activity Relationship Study of the XIP Quorum Sensing Pheromone in Streptococcus mutans Reveal Inhibitors of the Competence Regulon
Author(s):		Bikash CR; Tal-Gan Y;
Address:		"Department of Chemistry, University of Nevada, Reno, 1664 North Virginia Street, Reno, Nevada 89557, United States"
Journal Title:		ACS Chem Biol
Year:		2020
Volume:		20201002
Issue:		10
Page Number:		2833 - 2841
DOI:		10.1021/acschembio.0c00650
ISSN/ISBN:		1554-8937 (Electronic) 1554-8929 (Print) 1554-8929 (Linking)
Abstract:		"The 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"
Keywords:		Bacterial Proteins/chemical synthesis/genetics/*pharmacology Molecular Structure Peptides/chemical synthesis/genetics/*pharmacology Pheromones/chemical synthesis/genetics/*pharmacology Point Mutation Quorum Sensing/*drug effects Regulon/*drug effects Stre;
Notes:		"MedlineBikash, Chowdhury Raihan Tal-Gan, Yftah eng R35 GM128651/GM/NIGMS NIH HHS/ Research Support, N.I.H., Extramural 2020/09/19 ACS Chem Biol. 2020 Oct 16; 15(10):2833-2841. doi: 10.1021/acschembio.0c00650. Epub 2020 Oct 2"