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Mechanistic basis of how LD-transpeptidases protect against outer membranedefects

Award Number: R01AI168159
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: 03/08/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Mechanistic basis of how LD-transpeptidases protect against outer membranedefects - Project Summary/Abstract The emergence of multidrug and extensively drug-resistant Gram-negative bacteria is a growing problem that threatens established antimicrobial treatment protocols. Acinetobacter baumannii is a critical threat pathogen notorious for its ability to rapidly develop multidrug resistance. A. baumannii causes hospital-acquired infections, which manifest as bacteremia, urinary tract and wound infections. In the US, an estimated 60% of hospital-acquired A. baumannii infections were multidrug-resistant, often including carbapenem resistance, which leaves colistin as the “last-resort” treatment option. However, colistin resistance has also emerged. There is an urgent need to understand intrinsic mechanisms that promote antibiotic resistance in A. baumannii to guide alternative antimicrobial strategies. Our preliminary work has identified two LD-transpeptidases that promote viability of colistin resistant lipooligosaccharide-deficient A. baumannii. Specifically, LD-transpeptidase-dependent cell envelope modifications are key for the resistance phenotype, where alternative crosslinks compensate for outer membrane defects. In this proposal, we will address three important questions to understand the function and regulation of LD-transpeptidases in A. baumannii, including (I) how does LD-transpeptidase activity counter otherwise lytic mechanical forces produced by outer membrane defects?; (II) how are LdtK lipoprotein substrates regulated in A. baumannii?; and (III) how do class A penicillin-binding proteins impact LD-transpeptidase activity in A. baumannii? Collectively, these studies will address key questions in bacterial physiology and cell envelope assembly, which will enable us to build a model of intrinsic factors in A. baumannii that contribute to multidrug resistance. Furthermore, these analyses will aid in the design of combinatorial drug regimens that target both essential outer membrane and peptidoglycan layers of the cell envelope, thus precluding resistance; consequently, our findings support the National Institute of Health mission, which aims to foster fundamental discoveries to reduce human disease.


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 = $437,203 )
2025	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	002	5	2/13/2025	NON-COMPETING CONTINUATION	$437,203
2025	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	001	3	12/20/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$138,722
2025	2023	UNIVERSITY OF TEXAS AT ARLINGTON	701 S NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Allergy and Infectious Diseases Research	000	2	12/20/2024	NON-COMPETING CONTINUATION	-$138,722
														Subtotal = $437,203

Issue Date FY: 2024 ( Subtotal = $514,324 )
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	001	3	11/30/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$227,504
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	003	4	5/24/2024	NON-COMPETING CONTINUATION	$43,677
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Allergy and Infectious Diseases Research	002	4	2/14/2024	NON-COMPETING CONTINUATION	$393,110
2024	2023	THE UNIVERSITY OF TEXAS AT ARLINGTON	701 S. NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Allergy and Infectious Diseases Research	000	2	11/30/2023	NON-COMPETING CONTINUATION	-$149,967
														Subtotal = $514,324

Issue Date FY: 2023 ( Subtotal = $438,656 )
2023	2023	THE UNIVERSITY OF TEXAS AT ARLINGTON	701 S. NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Allergy and Infectious Diseases Research	000	2	3/1/2023	NON-COMPETING CONTINUATION	$438,656
														Subtotal = $438,656

Issue Date FY: 2022 ( Subtotal = $464,886 )
2022	2022	THE UNIVERSITY OF TEXAS AT ARLINGTON	701 S. NEDDERMAN DR	ARLINGTON	TX	76019	TARRANT	USA	Allergy and Infectious Diseases Research	001	1	9/9/2022	NEW	$0
2022	2022	UNIVERSITY OF TEXAS AT ARLINGTON	400 S CORN ST	ARLINGTON	TX	76019	TARRANT	USA	Allergy and Infectious Diseases Research	000	1	3/7/2022	NEW	$464,886
														Subtotal = $464,886

Grand Total All Awards = $1,855,069

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Mechanistic basis of how LD-transpeptidases protect against outer membranedefects

Award Number: R01AI168159

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: 03/08/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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