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Surface Proteins of Gram-Positive Bacteria

Award Number: R01AI038897
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: 02/01/1996
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Surface Proteins of Gram-Positive Bacteria - ABSTRACT Staphylococcus aureus is a major cause of community- and hospital-acquired diseases. Infections with antibiotic-resistant MRSA strains are associated with increased mortality. To identify targets for anti-MRSA therapy, this proposal analyzes the trafficking of surface proteins, which is essential for S. aureus colonization and invasive disease. Surface proteins are anchored to the cell wall, a process that requires specific signals and targeting mechanisms. Sortase A recognizes the LPXTG motif in C-terminal sorting signals, which are cut and covalently linked to peptidoglycan. Two types of surface protein precursors are distinguished. Precursors with canonical signal peptides are deposited in the envelope at the cell poles. Precursors with YSIRKxxxGxxS motif signal peptides traffic to the cross-wall. Confined by septal membranes during cell division, the cross-wall separates newly divided cells. It represents the site of de novo peptidoglycan synthesis and is split for completion of the cell cycle. Here we report that lipoteichoic acid (LTA) is synthesized at septal membranes and required for septal secretion of YSIRKxxxGxxS precursors. During secretion, the YSIRKx peptide is removed from the precursor. We screened temperature-sensitive mutants for defects in YSIRKxxxGxxS precursor secretion and identified variants with mutations in secA, secG and pepV. secA mutants are defective for the transport of all precursors, polar and septal secretion. secG and pepV mutants exhibit defects in septal secretion. SecA co-purifies with YSIRKxxxGxxS precursors and with PepV. We will test the hypothesis that lipid products of LTA synthesis are critical for the activation of PepV at septal membranes. Although YSIRKxxxGxxS precursors associate with SecA, we predict that precursor complexes cannot activate SecYEG translocons unless the YSIRKx peptide is removed. Upon completion of the cross-wall, LtaS, the catalyst of LTA synthesis, is cut and released while the products of LTA synthesis are dispersed until the next cell division cycle. The proposal will analyze LtaS variants defective in LTA synthesis and LtaS cleavage and characterize the contributions of specific lipids and LtaS regulation for septal secretion. We will characterize YSIRKxxxGxxS precursors bound to SecA for their ability to activate translocons in the presence of specifc lipids and PepV and study precursor mutants for their ability to activate SecYEG translocons. Last, we will characterize the subcellular distribution of PepV, its association with septal lipids, ability to cleave YSIRKxxGxxS precursors and contribution to S. aureus colonization and pathogenesis.


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 = $405,000 )
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	29	5/16/2024	NON-COMPETING CONTINUATION	$40,500
2024	2024	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	29	12/15/2023	NON-COMPETING CONTINUATION	$364,500
														Subtotal = $405,000

Issue Date FY: 2023 ( Subtotal = $405,000 )
2023	2023	UNIVERSITY OF CHICAGO	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	28	11/29/2022	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2022 ( Subtotal = $405,000 )
2022	2022	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	27	12/28/2021	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2021 ( Subtotal = $405,000 )
2021	2021	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	26	12/14/2020	NON-COMPETING CONTINUATION	$405,000
														Subtotal = $405,000

Issue Date FY: 2020 ( Subtotal = $405,000 )
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	002	25	4/21/2020	COMPETING CONTINUATION	$2
2020	2020	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	25	1/24/2020	COMPETING CONTINUATION	$405,000
2020	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	24	4/21/2020	NON-COMPETING CONTINUATION	-$2
														Subtotal = $405,000

Issue Date FY: 2019 ( Subtotal = $389,432 )
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	24	11/20/2018	NON-COMPETING CONTINUATION	$389,432
2019	2019	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	24	7/24/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $389,432

Issue Date FY: 2018 ( Subtotal = $389,432 )
2018	2018	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	23	11/2/2017	NON-COMPETING CONTINUATION	$389,432
														Subtotal = $389,432

Issue Date FY: 2017 ( Subtotal = $389,432 )
2017	2017	UNIVERSITY OF CHICAGO, THE	5801 S ELLIS AVE	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	22	11/7/2016	NON-COMPETING CONTINUATION	$389,432
														Subtotal = $389,432

Issue Date FY: 2016 ( Subtotal = $389,432 )
2016	2016	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	21	11/2/2015	NON-COMPETING CONTINUATION	$389,432
														Subtotal = $389,432

Issue Date FY: 2015 ( Subtotal = $389,432 )
2015	2015	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	20	11/5/2014	COMPETING CONTINUATION	$389,432
2015	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	19	11/4/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $389,432

Issue Date FY: 2013 ( Subtotal = $355,555 )
2013	2013	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	19	5/13/2013	NON-COMPETING CONTINUATION	$355,555
														Subtotal = $355,555

Issue Date FY: 2012 ( Subtotal = $378,250 )
2012	2012	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	18	5/25/2012	NON-COMPETING CONTINUATION	$378,250
														Subtotal = $378,250

Issue Date FY: 2011 ( Subtotal = $378,250 )
2011	2011	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	17	6/9/2011	NON-COMPETING CONTINUATION	$378,250
														Subtotal = $378,250

Issue Date FY: 2010 ( Subtotal = $382,071 )
2010	2010	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	16	6/11/2010	COMPETING CONTINUATION	$382,071
														Subtotal = $382,071

Issue Date FY: 2009 ( Subtotal = $349,937 )
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	001	15	6/2/2009	NON-COMPETING CONTINUATION	$34,993
2009	2009	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	15	12/23/2008	NON-COMPETING CONTINUATION	$314,944
														Subtotal = $349,937

Issue Date FY: 2008 ( Subtotal = $349,937 )
2008	2008	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	14	12/27/2007	NON-COMPETING CONTINUATION	$349,937
														Subtotal = $349,937

Issue Date FY: 2007 ( Subtotal = $356,715 )
2007	2007	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	13	1/31/2007	NON-COMPETING CONTINUATION	$356,715
														Subtotal = $356,715

Issue Date FY: 2006 ( Subtotal = $367,369 )
2006	2006	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Allergy and Infectious Diseases Research	000	12	1/26/2006	NON-COMPETING CONTINUATION	$367,369
														Subtotal = $367,369

Issue Date FY: 2005 ( Subtotal = $376,210 )
2005	2005	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Microbiology and Infectious Diseases Research	000	11	11/29/2004	COMPETING CONTINUATION	$376,210
														Subtotal = $376,210

Issue Date FY: 2004 ( Subtotal = $337,762 )
2004	2004	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Microbiology and Infectious Diseases Research	000	10	12/19/2003	NON-COMPETING CONTINUATION	$337,762
														Subtotal = $337,762

Issue Date FY: 2003 ( Subtotal = $337,762 )
2003	2003	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Microbiology and Infectious Diseases Research	000	9		NON-COMPETING CONTINUATION	$337,762
														Subtotal = $337,762

Issue Date FY: 2002 ( Subtotal = $337,762 )
2002	2002	UNIVERSITY OF CHICAGO	1225 EAST 60TH ST	CHICAGO	IL	60637	COOK	USA	Microbiology and Infectious Diseases Research	000	8	2/14/2002	NON-COMPETING CONTINUATION	$337,762
														Subtotal = $337,762

Grand Total All Awards = $9,349,144

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Surface Proteins of Gram-Positive Bacteria

Award Number: R01AI038897

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: 02/01/1996

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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