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Antibiotics : Studies on the Biological Mechanisms of Antibiotics

Award Number: R01AI149778
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: 08/05/2025
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Antibiotics : Studies on the Biological Mechanisms of Antibiotics - Project Summary/Abstract Antibiotic-resistant Gram-negative infections pose a major threat to human health. Gram-negative pathogens are intrinsically resistant to most clinically used classes of antibiotics due to the presence of an outer membrane that prevents antibiotic entry. Many Gram-negative pathogens, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, and E. coli, are now multi-drug resistant and can only be killed by colistin, an old antibiotic that was previously almost abandoned because it has dose-limiting toxicity. My lab played a large role in discovering the machines that assemble the Gram-negative outer membrane and has developed a comprehensive set of in vitro and in vivo tools to study outer-membrane assembly. Here, we will use our existing tools as well as new approaches to elucidate the mechanisms of action of two peptide antibiotics that target the lipopolysaccharide transport (Lpt) pathway, thanatin and murepavadin. The molecular mechanisms by which these compounds disrupt outer membrane assembly remain poorly understood. We hypothesize that a molecular understanding of how these compounds block lipopolysaccharide transport will enable the development of analogs with more promising properties as drugs. In Aims I and II, we will address the mechanism of action of thanatin using a range of biophysical and biochemical assays, including single molecule TIRF microscopy in living cells, in vitro biochemical assays that monitor different steps in LPS transport, and in vivo crosslinking assays that monitor LPS transport in cells. In Aim III, we will investigate the mechanism of action of murepavadin, and we will characterize the Pseudomonas aeruginosa multiprotein complex that we propose it targets. Using cyclic peptides, we have recently established that this multiprotein complex is a valid therapeutic target in Acinetobacter baumannii to treat Carbapenem-resistant Acinetobacter baumannii (CRAB) infections, so we will also use the Pseudomonas multiprotein complex in a screen to identify other antimicrobial peptides that may share a similar mechanism of action. In this way, the fundamental knowledge we obtain about how thanatin and murepavadin function could enable discovery of other classes of compounds to expand the spectrum of antibiotic-resistant Gram-negative pathogens that are susceptible to lipopolysaccharide transport inhibitors.


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 = $760,956 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	22	8/4/2025	COMPETING CONTINUATION	$761,164
2025	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	21	4/21/2025	NON-COMPETING CONTINUATION	-$208
														Subtotal = $760,956

Issue Date FY: 2024 ( Subtotal = $632,039 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	21	5/16/2024	NON-COMPETING CONTINUATION	$63,204
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	21	11/27/2023	NON-COMPETING CONTINUATION	$568,835
														Subtotal = $632,039

Issue Date FY: 2023 ( Subtotal = $632,039 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	20	11/23/2022	NON-COMPETING CONTINUATION	$632,039
														Subtotal = $632,039

Issue Date FY: 2022 ( Subtotal = $632,039 )
2022	2022	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	19	11/17/2021	NON-COMPETING CONTINUATION	$632,039
														Subtotal = $632,039

Issue Date FY: 2021 ( Subtotal = $632,039 )
2021	2021	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	18	11/20/2020	NON-COMPETING CONTINUATION	$632,039
														Subtotal = $632,039

Issue Date FY: 2020 ( Subtotal = $628,317 )
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	001	17	5/6/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$208
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	002	17	6/1/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2020	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Allergy and Infectious Diseases Research	000	17	11/29/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$628,109
														Subtotal = $628,317

Grand Total All Awards = $3,917,429

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Antibiotics : Studies on the Biological Mechanisms of Antibiotics

Award Number: R01AI149778

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: 08/05/2025

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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