Thursday, November 21, 2024 11/21/2024

Dynamics and Regulation of Peptidoglycan Cell Wall Synthesis in the Superbug Streptococcus pneumoniae

Award Number: R35GM131767
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Peptidoglycan (PG) is the mesh-like scaffolding that determines the shape and size of bacterial cells and protects them from osmotic shock. In Gram-positive bacteria, thick PG provides the outer cellular layer to which wall- teichoic acids, capsule, and extracellular proteins are covalently attached. The human respiratory pathogen Streptococcus pneumoniae (pneumococcus) has emerged as a leading model for PG synthesis and its regulation in ovoid-shaped Gram-positive bacteria. Pneumococcal PG synthesis shows fundamental differences from PG synthesis in rod-shaped and spherical bacteria. Most notably, PG synthesis is zonal and carried out by two separable PG synthase nanomachines confined to the midcell of dividing pneumococcal cells. The septal PG synthase (bPBP2x:FtsW) locates to the leading edge of the closing septal annulus, while the elongasome PG synthase (bPBP2b:RodA with RodZ, MreCD) locates to the outer rim of the septal annulus and pushes peripheral PG outward. Both the septal and elongasome PG synthases move circumferentially at midcell driven by PG synthesis, but not by FtsZ treadmilling. This project builds on previous findings to address the most important current questions about PG synthesis in S. pneumoniae. One set of questions centers on the functions and regulation of the three Class A PBP PG synthases (aPBP1a, aPBP1b, aPBP2a) in exponentially growing and stressed pneumococcal cells, about which relatively little is known. By using a comprehensive approach that includes innovative assays of septal and elongation PG synthesis rates in live cells, single-molecule (sm) motion dynamics, and high-resolution microscopy, we will determine the contributions of the aPBPs to PG synthesis and how their dynamics and localization are altered by mutational changes and cell-wall stress. Unbiased and directed approaches will be used to identify aPBP interactors at different stages of division and how these interactions regulate aPBP functions. A second set of questions center on the mechanisms that organize and regulate the septal and elongasome PG synthase nanomachines. We will determine mechanisms that organize circumferential motion and nodal distributions of PG synthases at midcell. We will also determine the assembly pathway of the septal divisome in early-divisional cells and the mechanisms by which the septal and elongasome PG synthesis machines separate and are regulated later in division. We will continue studies of newly discovered mechanisms that link PG synthase functions to the availability of PG precursor metabolites and to second messengers. A third set of questions concerns the roles, interactions, and regulation of the FtsEX:PcsB hydrolase in PG remodeling and the MpgB and MpgA muramidases in PG-chain release in septal and elongasome PG synthesis, respectively. Altogether, this project will fill in major knowledge gaps about the dynamics, functions, and regulation of aPBPs, about the organization and regulation of septal and elongasome PG synthesis, and about PG remodeling and hydrolysis in S. pneumoniae, add significantly to the PG synthesis field in general, and reveal additional vulnerabilities and targets for new antibiotic and vaccine development.


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 = $0 )
2025	2024	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Biomedical Research and Research Training	000	6	11/6/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $666,807 )
2024	2024	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Biomedical Research and Research Training	000	6	7/17/2024	COMPETING CONTINUATION	$666,807
														Subtotal = $666,807

Issue Date FY: 2023 ( Subtotal = $655,028 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Biomedical Research and Research Training	000	5	7/10/2023	NON-COMPETING CONTINUATION	$655,028
														Subtotal = $655,028

Issue Date FY: 2022 ( Subtotal = $655,028 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Biomedical Research and Research Training	000	4	6/29/2022	NON-COMPETING CONTINUATION	$655,028
														Subtotal = $655,028

Issue Date FY: 2021 ( Subtotal = $655,028 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVE	BLOOMINGTON	IN	47405	MONROE	USA	Biomedical Research and Research Training	000	3	7/16/2021	NON-COMPETING CONTINUATION	$655,028
														Subtotal = $655,028

Issue Date FY: 2020 ( Subtotal = $655,028 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	107 S INDIANA AVENUE	BLOOMINGTON	IN	47405	MONROE	USA	Biomedical Research and Research Training	000	2	7/31/2020	NON-COMPETING CONTINUATION	$655,028
														Subtotal = $655,028

Issue Date FY: 2019 ( Subtotal = $208,126 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	BRYAN HALL 107 S INDIANA AVENUE	BLOOMINGTON	IN	47405	MONROE	USA	Biomedical Research and Research Training	000	1	9/4/2019	NEW	$208,126
														Subtotal = $208,126

Grand Total All Awards = $3,495,045

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Dynamics and Regulation of Peptidoglycan Cell Wall Synthesis in the Superbug Streptococcus pneumoniae

Award Number: R35GM131767

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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