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Molecular Investigation of Bacterial Penicillin-Binding Protein Activity and Inhibition

Award Number: F31AI197293
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/20/2026
PERIOD OF PERFORMANCE END DATE: 04/19/2028

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Molecular Investigation of Bacterial Penicillin-Binding Protein Activity and Inhibition - ABSTRACT Bacteria shield themselves from the exterior environment with a rigid cell wall. The major structural component of this exoskeleton is the mesh-like peptidoglycan (PG), a heteropolymer composed of glycan strands and crosslinked stem peptides. Glycan strand polymerization and transpeptidation are catalyzed by penicillin-binding proteins (PBPs). Organisms express multiple PBP isoforms with varied spatiotemporal activity. Transpeptidation is inhibited by the b-lactams, a family of covalent inhibitors that mimic the terminal dipeptide structure of the nascent PG monomer; PBP inhibition results in growth abnormalities and cell lysis. Despite the therapeutic successes of b-lactam antibiotics, the current antimicrobial resistance crisis underscores the importance of understanding of PBP activity and inhibition, and cell wall composition more broadly. The Carlson Group studies PBP activity with chemical probes; however, achieving isoform selectivity is difficult due to spatial conservation of the transpeptidase active site. Specifically, the field lacks a comprehensive description of how conserved motifs in this active site mediate substrate and inhibitor binding. There is also a lack of understanding of how changes in the PBP activity profile alter PG composition. While nonuniformity of PG composition has been demonstrated in the context of bacterial resistance and host immune response to infection, a lack of bioinformatic methods for the unbiased identification of PG fragments impedes analyses of cell wall digests using liquid chromatography coupled to mass spectrometry (LC-MS). To address these outstanding questions in PBP activity and cell wall maintenance, the proposed research will use an alanine scan to map and quantify the contribution of conserved active site motifs in PBP2x from the Gram-positive pathogen Streptococcus pneumoniae to native substrate processing and b-lactam inhibition. Following initial assessment with a commercially available probe, this approach will be extended to a chemically diverse suite of b-lactams in live cell, in vitro, and in silico experiments to clarify how the active site permits occupancy of multiple inhibitor classes. Additionally, this project will use activity-based protein profiling and LC- MS/MS analyses to investigate how conditions mimicking the acidic infection microenvironment perturb PBP activity and PG composition. This work will be coupled to experiments probing the effects of transpeptidase inhibition and PBP deletion on PG structural diversity. Bioinformatic analyses of LC-MS/MS data will serve as crucial validation of the application of -omics strategies to interrogate PG composition. Ultimately, these aims will provide insight into key mediators of cell wall synthesis and maintenance, inform understanding of how bacteria leverage cell wall perturbations as defense mechanisms to evade antimicrobial threats, and inspire future probe design. The training plan will facilitate instruction in chemical biology, computational biochemistry, and bioinformatic -omics analyses through education in the group of Erin Carlson, and through collaborations at the University of Minnesota.


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: 2026 ( Subtotal = $50,114 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	001	1	4/15/2026	NEW	$576
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	002	1	4/15/2026	NEW	$0
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Allergy and Infectious Diseases Research	000	1	3/27/2026	NEW	$49,538
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Molecular Investigation of Bacterial Penicillin-Binding Protein Activity and Inhibition

Award Number: F31AI197293

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/20/2026

PERIOD OF PERFORMANCE END DATE: 04/19/2028

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