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The Cell Envelope of the Multi-Drug Resistant Pathogen Acinetobacter baumannii

Award Number: R01AI150098
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: 02/25/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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The Cell Envelope of the Multi-Drug Resistant Pathogen Acinetobacter baumannii - ABSTRACT The increasing rise in antibiotic resistance and the diminished discovery of new antimicrobials threatens global healthcare. Of particular concern are Gram-negative pathogens, as these organisms are intrinsically resistant to multiple classes of antibiotics and the discovery of novel drugs targeting these bacteria has remained challenging. The innate resistance of these organisms is provided primarily by their outer membrane (OM), a defining feature of Gram negatives that encapsulates their peptidoglycan layer. Unlike the inner membrane (IM) that is composed solely of glycerophospholipids (GPLs), the OM is asymmetrical with GPLs found in the inner leaflet and lipopolysaccharide (LPS) localized to the outer leaflet. This unique membrane organization affords protection from large polar molecules, as well as lipophilic compounds, creating an impervious barrier. Remarkably, the high-priority Gram-negative pathogen Acinetobacter baumannii can completely inactivate LPS biosynthesis as an alternative mechanism of resistance to the “last-resort” polymyxin antibiotics. The primary objective of this application is to investigate the mechanisms required for maintenance of the cell envelope of A. baumannii, regardless of LPS status. While the benefit of an asymmetric OM relative to a GPL bilayer is apparent due to the impermeable barrier it provides, the lack of LPS essentiality in A. baumannii can be used as a tool to explore novel mechanisms of OM stability in both the presence and absence of LPS. For Aim 1, we will investigate the role of surface lipoproteins that are induced during envelope stress and that are prominent during LPS-deficiency. We will also investigate how these proteins are transported across the OM. Aim 2 focuses on the characterization of two glycosyltransferases required for the tandem transfer of sugars during LPS synthesis, a unique mechanism in the assembly of a bacterial glycoconjugate. Finally, in Aim 3, we will characterize a novel OM cardiolipin synthase and how it impacts OM integrity. An OM cardiolipin synthase challenges current dogma that dictates all major GPLs are synthesized at the cytoplasmic face of the IM. Completion of the Aims will provide novel insights into cell envelope biogenesis and promote the development of novel therapeutics targeting Gram-negative pathogens.


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 = $579,302 )
2026	2026	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	7	1/9/2026	NON-COMPETING CONTINUATION	$579,302
														Subtotal = $579,302

Issue Date FY: 2025 ( Subtotal = $576,282 )
2025	2025	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	6	12/4/2024	COMPETING CONTINUATION	$576,282
2025	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	001	5	5/5/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $576,282

Issue Date FY: 2024 ( Subtotal = $539,322 )
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	5	1/4/2024	NON-COMPETING CONTINUATION	$485,390
2024	2024	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	001	5	5/28/2024	NON-COMPETING CONTINUATION	$53,932
														Subtotal = $539,322

Issue Date FY: 2023 ( Subtotal = $539,322 )
2023	2023	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	4	1/9/2023	NON-COMPETING CONTINUATION	$539,322
														Subtotal = $539,322

Issue Date FY: 2022 ( Subtotal = $539,322 )
2022	2022	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	3	12/17/2021	NON-COMPETING CONTINUATION	$539,322
														Subtotal = $539,322

Issue Date FY: 2021 ( Subtotal = $539,322 )
2021	2021	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	2	1/12/2021	NON-COMPETING CONTINUATION	$539,322
														Subtotal = $539,322

Issue Date FY: 2020 ( Subtotal = $539,322 )
2020	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	1	2/24/2020	NEW	$539,322
														Subtotal = $539,322

Grand Total All Awards = $3,852,194

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The Cell Envelope of the Multi-Drug Resistant Pathogen Acinetobacter baumannii

Award Number: R01AI150098

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: 02/25/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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