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Multiscale Modeling of B. Anthracis Surface Layer Assembly and Depolymerization by Nanobodies

Award Number: R21AI168838
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Alternative strategies to conventional antibiotics are needed to combat rising antibiotic resistance in bacteria. Therapeutics that target virulence factors would instead disarm bacteria and mitigate the risk of developing antibiotic resistance. In this proposal, we investigate the disruption of bacterial surface layer proteins (SLPs), which self-assemble into a para-crystalline surface layer (S-layer), a virulence factor that mediates bacterial aggregation, adhesion, and protection. Nanobodies, which exhibit low immunogenicity in humans, and are easier to purify and deliver compared to monoclonal antibodies, were recently demonstrated to depolymerize S- layers in the case of Bacillus anthracis, which led to complete survival in mice models under sustained treatment. Our scientific premise is that nanobody-based inhibition of S-layers is a viable antivirulence strategy once tuned for each bacterial pathogen. We propose to leverage our multiscale computer simulation expertise to identify the as-yet unknown mechanism of action and to determine sequence motifs that enhance nanobody-induced S-layer depolymerization in Bacillus anthracis. Our aims include (1) verification that depolymerization is induced by S-layer rigidification through the use of coarse-grained modeling and simulation and (2) determination of nanobodies with improved antivirulence by computationally tailoring existing nanobodies. The computational protocols developed herein are systematic and generalizable beyond Bacillus anthracis. We expect our findings and computational tools to extend to other SLP-expressing bacteria, including urgent antibiotic-resistant threats such as Clostridioides difficile, and aid the global fight against antibiotic-resistant bacteria.


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: 2023 ( Subtotal = $215,360 )
2023	2023	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	2	4/3/2023	NON-COMPETING CONTINUATION	$215,360
														Subtotal = $215,360

Issue Date FY: 2022 ( Subtotal = $177,718 )
2022	2022	TRUSTEES OF THE COLORADO SCHOOL OF MINES	1500 ILLINOIS ST	GOLDEN	CO	80401	JEFFERSON	USA	Allergy and Infectious Diseases Research	000	1	4/28/2022	NEW	$177,718
														Subtotal = $177,718

Grand Total All Awards = $393,078

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Multiscale Modeling of B. Anthracis Surface Layer Assembly and Depolymerization by Nanobodies

Award Number: R21AI168838

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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