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Elucidating altered lipid pathways in daptomycin-resistant pathogens

Award Number: K22AI143919
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 06/12/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Elucidating altered lipid pathways in daptomycin-resistant pathogens - Project Summary Alteration of membrane lipids, particularly the reduction of total phosphatidylglycerols (PGs), is a common daptomycin resistance phenotype across many species of Gram-positive bacteria. These modifications to membrane lipid content and composition can occur through direct genetic mutations in lipid biosynthetic pathways or indirect mutations in cell envelope stress response systems that regulate expression of membrane and cell wall biosynthesis genes. We have previously characterized the altered membrane lipids in daptomycin- resistant strains of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and Corynebacterium striatum and found that: i) daptomycin resistance also significantly affected non-PG lipids, and ii) the changes manifested only in membrane lipids with specific fatty acid compositions in MRSA and VRE. Lipid biosynthesis is a promising target for the development of novel therapies for the treatment of daptomycin resistance due to the lipid-dependent mechanism of daptomycin’s bactericidal action and the differences between eukaryotic and prokaryotic lipid biosynthetic pathways. However, the membrane lipidomes of Gram-positive bacteria are diverse in the variety and ratios of lipid classes present and the fatty acid compositions of those lipids. This diversity presents a challenge to finding common lipid pathways that can be exploited to disrupt daptomycin resistance, but the central pathways of lipid synthesis and metabolism are likely to be conserved across diverse daptomycin-resistant species. The long-term goals of this project are to identify the common and differential pathways in lipid biosynthesis and metabolism that contribute to daptomycin resistance among different species of Gram-positive bacteria and to identify small molecule modulators of these pathways that can reverse daptomycin resistance. In Aim 1, we will elucidate common and differential pathways in lipid metabolism and biosynthesis that are modified in a diverse collection of bacterial pathogens with daptomycin resistance. We will also examine the fatty acid-dependent nature of lipid changes in daptomycin-resistant MRSA and VRE. In Aim 2, we will modulate daptomycin resistance with small molecules targeting lipid biosynthesis and metabolism and evaluate the effects of extracellular free fatty acids on daptomycin resistance. We expect that the pathways that are conserved among diverse bacteria species with daptomycin resistance will be universal targets for modulation with small molecules, and these small molecules will improve daptomycin susceptibility by affecting the lipids and fatty acids that favor daptomycin resistance. This project will provide new fundamental understanding of the molecular alterations that contribute to daptomycin resistance and identify novel small molecule interventions that can be adapted into effective therapeutics for treating infections from multiple species of daptomycin-resistant 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: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Allergy and Infectious Diseases Research	000	2	9/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $107,991 )
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	5/6/2021	NON-COMPETING CONTINUATION	$107,991
														Subtotal = $107,991

Issue Date FY: 2020 ( Subtotal = $161,266 )
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	001	1	8/10/2020	NEW	$11,316
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	6/12/2020	NEW	$149,950
														Subtotal = $161,266

Grand Total All Awards = $269,257

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Elucidating altered lipid pathways in daptomycin-resistant pathogens

Award Number: K22AI143919

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 06/12/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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