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Novel small molecule biosynthetic gene clusters in Streptococcus mutans and virulence of dental caries

Award Number: R00DE029527
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: 05/18/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Novel small molecule biosynthetic gene clusters in Streptococcus mutans and virulence of dental caries - Project Summary Dental caries is a global infectious disease impacting the lives of 80% of the human population. Severe early childhood caries (SECC) is of particular concern and characterized by extensive tooth decay that can dramatically affect the dental health of children under six years of age. This constitutes a significant economic burden, can have dramatic impact on the child’s well being and may contribute to overall health later in life. Streptococcus mutans is the bacterium most commonly associated with initiation of SECC and early childhood caries (ECC). Biosynthetic gene clusters (BGCs) in bacteria often encode genes for small molecules and other antimicrobial peptides. This research plan proposes to investigate a novel BGC (butyrolactone-ladderane hybrid, BL-BGC) of S. mutans from a high caries risk population to identify its impact on S. mutans virulence and survival traits. Preliminary data suggests the BL-BGC is significantly up regulated in dental caries and occurs in the most prevalent strain type of S. mutans within a high-caries risk study population. The hypothesis is that clinical S. mutans strains with the BL-BGC will have increased virulence properties and cariogenicity. Aim 1 will characterize phenotypes of clinical S. mutans strains containing the BL- BGC and their association with dental caries key virulence and survival traits using gene mutagenesis and in-vivo biofilm analysis. Aim 2 will determine the impact of BL-BGC on expression of virulence genes and metabolites in S. mutans biofilms using RNA-sequencing and metabolomics analysis. Aim 3 will determine the how BL-BGC impacts S. mutans colonization and virulence using animal models of dental caries. The proposed study will elucidate the role of BL-BGC in S. mutans virulence and fitness during the K99 phase. Metabolites produced by S. mutans with BL-BGC impacting key virulence traits will be purified and characterized in the R00 phase, providing new insights into S. mutans’ role in the pathogenesis of dental caries. Characterization of this and other BGCs may lead to new therapeutic targets designed to reduce, reverse, or even prevent SECC. The K99 phase of this award will provide the time and support for additional research training, building effective collaborations, enhancing professional development and submission of publications leading to a successful transition to an independent academic research appointment in the R00 phase. This study is unique in the use of BGCs from clinical S. mutans isolates from a high-risk caries population allowing for clinical translation of results and the use of metabolomics for identification of BL-BGC related compounds/metabolites. This study will enable an independent career path by establishing a multidisciplinary program utilizing molecular biology approaches to validate epidemiological associations, bridging these fields and advancing the knowledge of S. mutans virulence in caries.


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: 2025 ( Subtotal = $249,000 )
2025	2025	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Oral Diseases and Disorders Research	000	4	3/20/2025	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $249,000

Issue Date FY: 2024 ( Subtotal = $248,483 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Oral Diseases and Disorders Research	000	3	5/17/2024	EXTENSION WITH OR WITHOUT FUNDS	$248,483
														Subtotal = $248,483

Grand Total All Awards = $497,483

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Novel small molecule biosynthetic gene clusters in Streptococcus mutans and virulence of dental caries

Award Number: R00DE029527

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: 05/18/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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