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Biogenesis and Function of Streptococcus Pyogenes Cell Wall

Award Number: R01AI143690
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: 11/25/2019
PERIOD OF PERFORMANCE END DATE: 10/31/2025

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Biogenesis and Function of Streptococcus Pyogenes Cell Wall - Group A streptococcus (GAS, Streptococcus pyogenes) is a leading bacterial pathogen of the human pharynx and skin. In recent years, a striking resurgence in severe invasive GAS infections has been observed worldwide. GAS infections account for more than 650,000 cases of severe invasive disease annually. The invasive GAS infections, necrotizing fasciitis, cellulitis and erysipelas with concomitant scarlet fever and streptococcal toxic syndrome, are difficult to treat with antibiotics, and a GAS vaccine is urgently needed to combat this neglected disease. A major component of the GAS cell wall is the Group A Carbohydrate (GAC) covalently linked to peptidoglycan, consisting of a polyrhamnose backbone with N-acetylglucosamine (GlcNAc) side-chains. GAC is an attractive vaccine candidate due to its conserved expression in all GAS serotypes and the absence of its constitutive component, rhamnose, in humans. Our genetic, biochemical and structural studies identified two novel modifications of GAC glycans: glycerol phosphate modification of GAC and de-N-acetylation of the GAC linkage unit. The goal of this proposal is to characterize the mechanisms of GAC biosynthesis and modification, and elucidate the roles of cell wall modifications in antimicrobial resistance mechanisms and GAS pathogenesis. To help answer these questions we will employ a variety of genetic, biochemical, analytical and structural approaches. The function of cell wall modifications in GAS pathogenesis will be studied in ex vivo and in vivo models of GAS infection. The proposed studies provide a platform for design of a safe and effective vaccine against this important human pathogen and should have broad application to other streptococci which express similar cell wall polysaccharides. Since the enzymes of the GAC biosynthesis pathway are attractive drug targets, the proposed studies will have important implications for drug design.


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 = $382,500 )
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	001	5	5/15/2024	NON-COMPETING CONTINUATION	$38,250
2024	2024	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	5	10/26/2023	NON-COMPETING CONTINUATION	$344,250
														Subtotal = $382,500

Issue Date FY: 2023 ( Subtotal = $382,500 )
2023	2023	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	4	10/18/2022	NON-COMPETING CONTINUATION	$382,500
														Subtotal = $382,500

Issue Date FY: 2022 ( Subtotal = $380,280 )
2022	2022	UNIVERSITY OF KENTUCKY RESEARCH FOUNDATION, THE	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	3	11/23/2021	NON-COMPETING CONTINUATION	$380,280
														Subtotal = $380,280

Issue Date FY: 2021 ( Subtotal = $393,530 )
2021	2021	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	2	10/26/2020	NON-COMPETING CONTINUATION	$393,530
														Subtotal = $393,530

Issue Date FY: 2020 ( Subtotal = $382,500 )
2020	2020	UNIVERSITY OF KENTUCKY	500 S LIMESTONE 109 KINKEAD HALL	LEXINGTON	KY	40526	FAYETTE	USA	Allergy and Infectious Diseases Research	000	1	11/25/2019	NEW	$382,500
														Subtotal = $382,500

Grand Total All Awards = $1,921,310

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Biogenesis and Function of Streptococcus Pyogenes Cell Wall

Award Number: R01AI143690

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: 11/25/2019

PERIOD OF PERFORMANCE END DATE: 10/31/2025

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