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Antibiotics from nose and throat commensals that impact pathogen colonization

Award Number: R01AI101018
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: 08/01/2012
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Antibiotics from nose and throat commensals that impact pathogen colonization - Project Summary The great promise of human microbiome research is that managing microbiome composition will prevent and cure disease. To this end, our long-term goals are to identify molecular mechanisms that drive bacterial community dynamics in nasal and skin microbiota and to uncover new antibiotics for controlling pathogen colonization and infection. Previous research shows that nasal microbiome composition and Staphylococcus aureus nasal colonization are strongly impacted by environmental factors, including other members of the microbiome. However, the molecular underpinnings of this are largely unknown. This proposal focuses on Propionibacterium species that colonize the skin and nasal passages of most adult humans. Our overarching hypothesis is that cutaneous Propionibacterium species produce antibiotics that control colonization by and proliferation of S. aureus and pathogenic Streptococcus species. Our preliminary data indicate that cutaneous Propionibacterium encode a distinct set of biosynthetic gene clusters (BGCs) predicted to produce antibiotics. We recently purified and structurally characterized one we call propimycin, a Propionibacterium-produced thiopeptide with potent activity against S. aureus in vitro. Our objectives are to identify more of these antibiotics and to define their role in shaping microbiome in vivo. Our rationale is that these Propionibacterium-produced compounds are likely to be important drivers of skin/nasal microbiome composition and, thus, key to developing new approaches to manage microbiome to promote health. To date, we have identified two Propionibacterium antibiotic BGCs specifically induced by coculture with S. aureus, propimycin and a nonribosomal peptide (NRP) that is widely distributed on human skin based on metagenomic data. We will use chemistry, bioinformatic, transcriptomic and bacterial genetics approaches to achieve the Specific Aims of this proposal: (1) determine the role of propimycin on human skin, focusing on skin follicles; (2A) purify and solve the structure of the NRP, a second candidate Propionibacterium antibiotic predicted to have anti-S. aureus activity; (2B) determine the mechanism of the NRP's increased transcription in response to Staphylococcus; and (3) identify additional candidate Propionibacterium antibiotic BGCs expressed in the context of the skin or nasal microbiome. Our strategy has four main innovations: (1) doing molecular experimental work in cutaneous Propionibacterium, which are recalcitrant to genetic manipulation; (2) using sebaceous plugs from human skin follicles to develop ex vivo assays to assess the impact of Propionibacterium antibiotics on S. aureus; (3) coupling a genetic screen in a heterologous system with next-gen-sequencing-based identification of promoters bound by candidate Propionibacterium acnes transcriptional regulators; and (4) using interactions between commensal Propionibacterium and the pathogens S. aureus and S. pneumoniae to uncover molecular mechanisms governing microbiome community dynamics. The significance will be to uncover new antibiotics produced by Propionibacterium and define their role in structuring skin/nasal microbial communities.


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 = -$3,357 )
2024	2021	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	9	8/2/2024	NON-COMPETING CONTINUATION	-$3,357
														Subtotal = -$3,357

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	9	12/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $484,679 )
2021	2021	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	9	12/10/2020	NON-COMPETING CONTINUATION	$484,679
2021	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	003	8	6/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$595,103
2021	2019	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	7	6/4/2021	NON-COMPETING CONTINUATION	-$532,744
2021	2018	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	6	6/4/2021	NON-COMPETING CONTINUATION	-$62,359
														Subtotal = $484,679

Issue Date FY: 2020 ( Subtotal = $497,393 )
2020	2020	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	001	8	4/22/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$497,393
2020	2019	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	7	4/22/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $497,393

Issue Date FY: 2019 ( Subtotal = $532,744 )
2019	2019	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	7	12/11/2018	NON-COMPETING CONTINUATION	$532,744
														Subtotal = $532,744

Issue Date FY: 2018 ( Subtotal = $531,603 )
2018	2018	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	6	12/22/2017	NON-COMPETING CONTINUATION	$531,603
														Subtotal = $531,603

Issue Date FY: 2017 ( Subtotal = $542,086 )
2017	2017	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	5	6/8/2017	COMPETING CONTINUATION	$0
2017	2017	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	5	1/10/2017	COMPETING CONTINUATION	$542,086
2017	2015	FORSYTH DENTAL INFIRMARY FOR CHILDREN	245 FIRST ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	4	12/21/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $542,086

Issue Date FY: 2015 ( Subtotal = $442,757 )
2015	2015	Forsyth Dental Infirmary for Children Forsyth Institute	140 FENWAY	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	6/24/2015	NON-COMPETING CONTINUATION	$442,757
														Subtotal = $442,757

Issue Date FY: 2014 ( Subtotal = $442,247 )
2014	2014	Forsyth Dental Infirmary for Children Forsyth Institute	140 FENWAY	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	7/1/2014	NON-COMPETING CONTINUATION	$442,247
														Subtotal = $442,247

Issue Date FY: 2013 ( Subtotal = $414,710 )
2013	2013	Forsyth Dental Infirmary for Children Forsyth Institute	140 FENWAY	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	7/15/2013	NON-COMPETING CONTINUATION	$414,710
														Subtotal = $414,710

Issue Date FY: 2012 ( Subtotal = $463,579 )
2012	2012	Forsyth Dental Infirmary for Children Forsyth Institute	140 FENWAY	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	8/20/2012	NEW	$463,579
														Subtotal = $463,579

Grand Total All Awards = $4,348,441

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Antibiotics from nose and throat commensals that impact pathogen colonization

Award Number: R01AI101018

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: 08/01/2012

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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