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The Structural and Functional Determination of Streptococcus mutans Adherence

Award Number: R01DE029007
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2025

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The Structural and Functional Determination of Streptococcus mutans Adherence - Dental caries is a polymicrobial disease that affects much of the human population worldwide, where the harmony of a cooperative eco-organization shifts towards a dysbiotic framework with overrepresentation of pathogenic microorganisms, particularly by Streptococcus mutans (SM). For planktonic SM, adhesion to tooth surface and/or dental biofilms is a crucial step in the pathogenesis of dental caries, and SM has evolved (i) SM- host and (ii) SM-microbial interactions, which are mediated through its surface proteins (adhesins). SM’s adhesion mediated interactions include: (A) The recent discovery of redundant high affinity binding of SM’s adhesins to the scavenger receptor cysteine rich domains (SRCR) of the salivary glycoprotein 340 (Gp340), which promotes caries susceptibility in the SM-host interface; and (B) The revelation of SM’s adhesin required for the SM-Candida albicans (CA) biofilm formation and acid production, which enhances cariogenicity in early childhood caries in the SM-microbial interface. Together these have revealed previously unknown interactions by once thought to be well-known and well-characterized adhesins on SM. Yet the key unanswered question remains, “how does SM mediate such redundant, but specific binding to host proteins and to other microbes?” The goal of this application is to determine the specific motif(s) and/or molecular mechanism(s) that drive SM’s adherence, particularly how they enable binding to multiple ligands. Our structural and functional studies show that SM’s surface adhesins mediate these attachments primarily via two major structural domains, the V- and C-fold. We hypothesize that “the V- and C-fold present on the surface adhesins of SM mediate specific interactions through common binding motif(s) that are crucial for biofilm formation and microbial colonization”. We will address our hypothesis through three specific aims (SAs) by (a) mapping the adherence motif(s) on the V-fold (SA1) and (b) C-fold (SA2) of oral streptococcal adhesins, and (c) investigating the role of SM’s adhesins in the SM-Candida albicans (CA) interface (SA3). The results from this multi-PD/PI study will (i) Determine the binding-motif(s)/mechanisms globally adopted by the V- and C-fold among SM’s adhesins; (ii) Determine the presence of distinct and/or overlapping adherence sites for various ligands; (iii) Provide a comparative analysis of the V- and C-fold of various adhesins from mutans and viridans streptococci, revealing species-specific differences in their binding-motifs/mechanisms; (iv) Characterize the role of SM adhesins at the SM-CA interface; and (v) Elucidate alternations in the microbial ecology modulated by SM’s V- and C-folds, particularly as they relate to dental caries. Our proposed structural analyses, genetic manipulation of key adhesion motif(s) and animal model studies will determine the adherence mechanisms and address the knowledge gap on SM’s V- and C-fold, particularly their crucial role in promoting colonization and virulence. The results will enable future development of selective combinatorial therapeutics to prevent SM’s adherence to host and microbes.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $413,974 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	5	6/7/2024	NON-COMPETING CONTINUATION	$33,794
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	5	2/26/2024	NON-COMPETING CONTINUATION	$380,180
														Subtotal = $413,974

Issue Date FY: 2023 ( Subtotal = $422,423 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	4	2/14/2023	NON-COMPETING CONTINUATION	$422,423
														Subtotal = $422,423

Issue Date FY: 2022 ( Subtotal = $418,200 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	3	1/27/2022	NON-COMPETING CONTINUATION	$380,179
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	3	4/22/2022	NON-COMPETING CONTINUATION	$38,021
														Subtotal = $418,200

Issue Date FY: 2021 ( Subtotal = $422,423 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	001	2	2/19/2021	NON-COMPETING CONTINUATION	$42,243
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	2	1/28/2021	NON-COMPETING CONTINUATION	$380,180
														Subtotal = $422,423

Issue Date FY: 2020 ( Subtotal = $422,423 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Oral Diseases and Disorders Research	000	1	2/21/2020	NEW	$422,423
														Subtotal = $422,423

Grand Total All Awards = $2,099,443

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The Structural and Functional Determination of Streptococcus mutans Adherence

Award Number: R01DE029007

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2025

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