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Envelope biogenesis in Escherichia coli and Pseudomonas aeruginosa

Award Number: R01AI083365
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: 01/01/2010
PERIOD OF PERFORMANCE END DATE: 12/31/2029

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Envelope biogenesis in Escherichia coli and Pseudomonas aeruginosa - SUMMARY A major goal of bacterial cell biology is to understand the mechanisms underlying the assembly and growth of the cell envelope. In addition to addressing a fundamental biological question, studies in this area have significant consequences for human health because the envelope serves as both a major target for antibiotics and, in the case of Gram-negative bacteria, a formidable barrier that prevents drugs from reaching their target. Thus, understanding of the mechanisms controlling the construction of the Gram-negative envelope will help identify new vulnerabilities in the process to target for antibiotic development. The Gram-negative envelope consists of two membranes, an inner membrane (IM) and outer membrane (OM), with a thin layer of peptidoglycan (PG) cell wall sandwiched between them. The IM is a typical phospholipid (PL) bilayer whereas the OM has an asymmetric structure with PL in the inner leaflet and an outer leaflet composed of lipopolysaccharide (LPS) glycolipids. Lateral interactions between LPS molecules provide the barrier function to the OM, preventing entry of both large polar molecules and small hydrophobic molecules. The PG layer fortifies the IM and prevents osmotic lysis. Studies of envelope biogenesis in many labs over the last several decades have identified and characterized most proteins essential for cell surface assembly in proteobacterial cells. The next major challenge in the field is to elucidate the mechanisms by which biogenesis of the different envelope layers is coordinated to promote uniform surface growth and maintain the OM permeability barrier. Therefore, the focus of this proposal is on defining the mechanisms that balance the supply of envelope subunits to ensure that each layer of the surface can be built at a similar rate. Balance in the supply of envelope components is critical because the overaccumulation of one component can induce toxic alterations to the envelope. Coordinating synthesis of envelope building blocks is also important because their synthesis pathways share common precursors such as: (i) acyl-ACP (acyl-carrier protein), the source of acyl chains for LPS and PLs, (ii) UDP-N-acetylglucosamine (UDP-GlcNAc), the source of sugar moieties for LPS and PG, and (iii) the lipid carrier undecaprenol-phosphate (C55P) used for surface glycan polymer biogenesis. Thus, if flux through these pathways is not balanced, the overproduction of one envelope component will indirectly impair the biogenesis of another, causing a damaging precursor deficit. Our work has recently revealed several novel mechanisms responsible for balancing the synthesis of envelope building blocks in Escherichia coli and Pseudomonas aeruginosa. We have identified a conserved feedback mechanism governing C55P utilization by the cell wall synthesis pathway, a potential regulatory system connecting PL and LPS synthesis in E. coli, and a regulatory interaction between LPS and PG synthesis enzymes in P. aeruginosa likely used to efficiently distribute UDP-GlcNAc between the pathways. The experiments described in this proposal will enhance our understanding of the molecular nature of these controls and reveal new regulatory pathways for further study.


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 = $632,819 )
2026	2026	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	17	1/7/2026	NON-COMPETING CONTINUATION	$632,819
														Subtotal = $632,819

Issue Date FY: 2025 ( Subtotal = $615,924 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	004	16	5/8/2025	COMPETING CONTINUATION	$0
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	003	16	5/5/2025	COMPETING CONTINUATION	$97,567
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	16	12/28/2024	COMPETING CONTINUATION	$615,924
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	15	5/5/2025	NON-COMPETING CONTINUATION	-$97,567
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	15	12/27/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $615,924

Issue Date FY: 2024 ( Subtotal = $535,006 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	15	5/16/2024	NON-COMPETING CONTINUATION	$53,500
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	15	12/13/2023	NON-COMPETING CONTINUATION	$481,506
														Subtotal = $535,006

Issue Date FY: 2023 ( Subtotal = $535,006 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	14	12/8/2022	NON-COMPETING CONTINUATION	$535,006
														Subtotal = $535,006

Issue Date FY: 2022 ( Subtotal = $535,006 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	13	1/24/2022	NON-COMPETING CONTINUATION	$535,006
														Subtotal = $535,006

Issue Date FY: 2021 ( Subtotal = $535,006 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	12	5/19/2021	NON-COMPETING CONTINUATION	$0
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	12	12/10/2020	NON-COMPETING CONTINUATION	$535,006
														Subtotal = $535,006

Issue Date FY: 2020 ( Subtotal = $535,006 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	002	11	7/8/2020	COMPETING CONTINUATION	$142,413
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	11	12/26/2019	COMPETING CONTINUATION	$535,006
2020	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	10	7/8/2020	NON-COMPETING CONTINUATION	-$142,413
														Subtotal = $535,006

Issue Date FY: 2019 ( Subtotal = $482,553 )
2019	2019	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	10	12/14/2018	NON-COMPETING CONTINUATION	$482,553
														Subtotal = $482,553

Issue Date FY: 2018 ( Subtotal = $482,553 )
2018	2018	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	9	12/27/2017	NON-COMPETING CONTINUATION	$482,553
														Subtotal = $482,553

Issue Date FY: 2017 ( Subtotal = $482,553 )
2017	2017	HARVARD COLLEGE, PRESIDENT & FELLOWS OF	25 SHATTUCK ST	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	8	12/21/2016	NON-COMPETING CONTINUATION	$482,553
														Subtotal = $482,553

Issue Date FY: 2016 ( Subtotal = $447,012 )
2016	2016	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	7	12/11/2015	NON-COMPETING CONTINUATION	$447,012
														Subtotal = $447,012

Issue Date FY: 2015 ( Subtotal = $447,012 )
2015	2015	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	6	11/12/2014	COMPETING CONTINUATION	$447,012
														Subtotal = $447,012

Issue Date FY: 2014 ( Subtotal = $413,398 )
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	5	6/4/2014	NON-COMPETING CONTINUATION	$41,340
2014	2014	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	5	12/12/2013	NON-COMPETING CONTINUATION	$372,058
														Subtotal = $413,398

Issue Date FY: 2013 ( Subtotal = $388,761 )
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	4	1/4/2013	NON-COMPETING CONTINUATION	$372,217
2013	2013	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	4	6/6/2013	NON-COMPETING CONTINUATION	$16,544
														Subtotal = $388,761

Issue Date FY: 2012 ( Subtotal = $413,749 )
2012	2012	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	3	1/27/2012	NON-COMPETING CONTINUATION	$413,749
														Subtotal = $413,749

Issue Date FY: 2011 ( Subtotal = $413,916 )
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	001	2	6/7/2011	NON-COMPETING CONTINUATION	$37,629
2011	2011	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	2	12/10/2010	NON-COMPETING CONTINUATION	$376,287
														Subtotal = $413,916

Issue Date FY: 2010 ( Subtotal = $421,665 )
2010	2010	HARVARD UNIVERSITY MEDICAL SCHOOL	643 HUNTINGTON AVENUE	BOSTON	MA	02115	SUFFOLK	USA	Allergy and Infectious Diseases Research	000	1	12/30/2009	NEW	$421,665
														Subtotal = $421,665

Grand Total All Awards = $8,316,945

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Envelope biogenesis in Escherichia coli and Pseudomonas aeruginosa

Award Number: R01AI083365

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: 01/01/2010

PERIOD OF PERFORMANCE END DATE: 12/31/2029

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