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Identification of Anti-Staphylococcus aureus Metabolites Produced by Dolosigranulum pigrum from the Human Nose

Award Number: R03AI182770
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/16/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Identification of Anti-Staphylococcus aureus Metabolites Produced by Dolosigranulum pigrum from the Human Nose - PROJECT SUMMARY Misuse of antibiotics leads to the emergence of multidrug-resistant pathogens and can perturb the endogenous microbiome, providing opportunities for secondary infection by pathobionts, including Staphylococcus aureus. The long-term goal of this work is to understand the chemical mechanisms used by Dolosigranulum pigrum, a beneficial bacterial species found in the human nose, to compete against co-occurring S. aureus, and to develop therapeutics against this pathobiont. The overall objectives in this application are to (i) isolate and identify ribosomally synthesized and post-translationally modified peptides (RiPPs) that are produced by D. pigrum to inhibit S. aureus and (ii) establish a genetic system for D. pigrum that will enable future research into this organism. The central hypothesis is that D. pigrum is a mutualist that defends its host in the nose against pathobionts, including S. aureus. The rationale for this project is that its successful completion will lead to the identification of candidate anti-S. aureus RiPPs from D. pigrum that could be developed into new therapeutics and open new avenues for research into the beneficial roles of D. pigrum in the nose. The central hypothesis will be tested by pursuing two specific aims: 1) Identify anti-S. aureus RiPPs produced by D. pigrum; and 2) Develop a genetic system in D. pigrum for deletion of BGCs and other genes of interest. Under Specific Aim 1, D. pigrum isolates will be cultured from nasal swab specimens. The D. pigrum isolates will be assessed for their ability to inhibit multiple S. aureus strains using co-culture plate inhibition assays under conditions mimicking the human nasal cavity. Metabolites will be extracted from D. pigrum cultures, purified, and characterized using mass spectrometry and nuclear magnetic resonance spectroscopy to determine the structure of bioactive anti-S. aureus RiPPs. For Specific Aim 2, a system to delete BGCs and other genes of interest will be established in D. pigrum. Electroporation, polyethylene glycol-mediated transformation, and intergeneric conjugation will be tested to identify an approach that can be used to introduce exogenous DNA into D. pigrum. Subsequently, targeted deletions of RiPP-encoding BGCs in D. pigrum will be performed through allelic exchange, and the resulting mutants will be tested in co-culture with S. aureus to verify the impact of specific BGCs on interspecies interactions. The research proposed in this application is innovative because it aims to identify anti-S. aureus RiPPs by uncovering the molecular mechanisms behind an ecologically relevant competitive interaction between D. pigrum and S. aureus. The proposed research is significant because it will address the critical need to identify novel therapeutics for S. aureus infections and aims to minimize disruption to the nasal microbiome, which is essential for preventing other opportunistic infections and maintaining overall health.


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: 2026 ( Subtotal = $0 )
2026	2025	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Allergy and Infectious Diseases Research	000	2	11/18/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $71,519 )
2025	2025	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Allergy and Infectious Diseases Research	000	2	12/4/2024	NON-COMPETING CONTINUATION	$71,519
														Subtotal = $71,519

Issue Date FY: 2024 ( Subtotal = $71,708 )
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Allergy and Infectious Diseases Research	000	1	2/16/2024	NEW	$64,537
2024	2024	OKLAHOMA STATE UNIVERSITY	401 WHITEHURST HALL	STILLWATER	OK	74078	PAYNE	USA	Allergy and Infectious Diseases Research	001	1	6/6/2024	NEW	$7,171
														Subtotal = $71,708

Grand Total All Awards = $143,227

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Identification of Anti-Staphylococcus aureus Metabolites Produced by Dolosigranulum pigrum from the Human Nose

Award Number: R03AI182770

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/16/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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