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Molecular mechanisms of peptidoglycan endopeptidase regulation

Award Number: R01GM130971
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Molecular mechanisms of peptidoglycan endopeptidase regulation - PROJECT SUMMARY Most bacteria maintain a cell wall, an essential, mesh-like structure mainly comprising the polysaccharide peptidoglycan (PG). Some of our most powerful antibiotics, the b-lactams (penicillins, carbapenems and cephalosporins) target enzymes required for cell wall synthesis and derive their efficacy from their ability to not only inhibit cell wall biogenesis, but also to actively cause its destruction. Cell wall destruction after exposure to b-lactams is mediated by “autolysins”, a group of enzymes (amidases, lytic transglycosylases and endopeptidase) with the capacity to cut a variety of chemical bonds within the PG mesh. Under normal growth conditions, autolysins engage in important cell wall remodeling functions, such as PG mesh expansion during cell elongation; how these functions are regulated to ensure proper PG maintenance is poorly understood. We have shown that in the diarrheal pathogen Vibrio cholerae, the endopeptidases (EPs) ShyA and ShyC are required for cell elongation during normal growth, but are also key factors mediating cell wall breakdown after exposure to beta lactam antibiotics. How ShyA and ShyC are regulated to ensure proper cell wall maintenance in the absence of antibiotics is unknown. Here, we propose experiments to build a thorough understanding of mechanisms of endopeptidase regulation in V. cholerae on multiple levels. Since M23 EPs are well-conserved throughout Bacteria, our experiments will likely yield insights with broad relevance to other pathogens. Leveraging extensive preliminary screens, we will i) establish how EPs are co-ordinated with PG synthesis, ii) interrogate the functional interaction between EPs and other autolysins, and iii) determine the role of proteolytic processing in EP activity regulation. Taken together, these experiments will provide us with an extensive framework of how bacteria maintain the balance between cell wall synthesis and remodeling, which could ultimately lead to the discovery of new potential targets for antibiotics that modulate autolysin activity.


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 = $345,455 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	6	8/12/2025	NON-COMPETING CONTINUATION	$345,455
														Subtotal = $345,455

Issue Date FY: 2024 ( Subtotal = $350,211 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	001	5	8/27/2024	COMPETING CONTINUATION	$350,211
2024	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	1/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $350,211

Issue Date FY: 2022 ( Subtotal = $304,801 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	4	8/5/2022	NON-COMPETING CONTINUATION	$304,801
														Subtotal = $304,801

Issue Date FY: 2021 ( Subtotal = $305,207 )
2021	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	3	8/6/2021	NON-COMPETING CONTINUATION	$305,207
														Subtotal = $305,207

Issue Date FY: 2020 ( Subtotal = $316,774 )
2020	2020	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	2	8/13/2020	NON-COMPETING CONTINUATION	$316,774
														Subtotal = $316,774

Issue Date FY: 2019 ( Subtotal = $333,154 )
2019	2019	CORNELL UNIVERSITY, INC	373 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Biomedical Research and Research Training	000	1	8/22/2019	NEW	$333,154
														Subtotal = $333,154

Grand Total All Awards = $1,955,602

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Molecular mechanisms of peptidoglycan endopeptidase regulation

Award Number: R01GM130971

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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