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Mechanistic details of key integral membrane enzymes for antimicrobial discovery

Award Number: R01GM114611
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Mechanistic details of key integral membrane enzymes for antimicrobial discovery - Project Summary Title: Mechanistic details of key integral-membrane enzymes for antimicrobial discovery The increasing number of antibiotic resistant strains of bacteria represents a significant threat to human health, making the development of novel therapeutic strategies critical. The major component of the bacterial cell wall is the peptidoglycan layer that is a unique meshwork providing essential structural support; therefore, identifying ways to weaken this layer is an ideal antibiotic strategy. Currently, numerous therapeutics target the peptidoglycan synthesis pathway and their use has been extremely successful in medicine. The enzymes involved in the pathway have been extensively characterized except in the case of the membrane components. Most notable are MraY and MurG, essential proteins that catalyze the membrane steps of peptidoglycan biosynthesis. There are a few known inhibitors of MraY, such as tunicamycin, demonstrating its potential as an antibiotic target; however, none of them has found usefulness in the clinic. Our group has developed efficient total synthesis schemes for two of the most promising natural products, capuramycin and muraymycin, and in the last funding period we have leveraged this to create novel compounds with improved therapeutic potential. In this proposal, we describe our plans to use our functional MraY homologs to solve structures in a lipid environment with various inhibitors and substrate analogs by EM and X-ray crystallography. We have developed a new assay for MurG that allowed us to identify novel inhibitors. We will further screen additional compounds and solve their structures with MurG. We will further explore the MurG interaction with the lipid bilayer and MraY. Our novel inhibitors, APPB and CPPB, have broad efficacy against bacterial pathogens and show potential as anti-cancer therapeutics. We will leverage the structural work to design the next round of compound libraries. The breadth of effectiveness leads us to pursue structures of other phosphotransferases, bacterial WecA and human DPAGT1, in complex with our compounds. This will allow for more targeted small molecule development. The aims are to 1) perform structural and mechanistic studies of MraY and the development of inhibitors, 2) carry out mechanistic and structural studies of MurG, and 3) develop novel and improved phosphotransferase inhibitors. Our combined team of structural biologists and synthetic chemists provides an innovative approach to achieve these important goals.


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 = -$25,048 )
2026	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	3/4/2026	NON-COMPETING CONTINUATION	-$25,048
														Subtotal = -$25,048

Issue Date FY: 2024 ( Subtotal = $540,243 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	7/1/2024	NON-COMPETING CONTINUATION	$442,563
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	001	8	8/27/2024	SUPPLEMENT FOR EXPANSION	$97,680
														Subtotal = $540,243

Issue Date FY: 2023 ( Subtotal = $442,563 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	7/14/2023	NON-COMPETING CONTINUATION	$442,563
														Subtotal = $442,563

Issue Date FY: 2022 ( Subtotal = $442,563 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	6/23/2022	NON-COMPETING CONTINUATION	$442,563
														Subtotal = $442,563

Issue Date FY: 2021 ( Subtotal = $459,438 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	002	5	9/19/2021	COMPETING CONTINUATION	$85
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	5	6/23/2021	COMPETING CONTINUATION	$459,438
2021	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	9/19/2021	NON-COMPETING CONTINUATION	-$85
														Subtotal = $459,438

Issue Date FY: 2019 ( Subtotal = $448,794 )
2019	2019	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	6/28/2019	NON-COMPETING CONTINUATION	$448,794
														Subtotal = $448,794

Issue Date FY: 2018 ( Subtotal = $448,794 )
2018	2018	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	7/27/2018	NON-COMPETING CONTINUATION	$448,794
														Subtotal = $448,794

Issue Date FY: 2017 ( Subtotal = $448,794 )
2017	2017	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	7/6/2017	NON-COMPETING CONTINUATION	$448,794
														Subtotal = $448,794

Issue Date FY: 2016 ( Subtotal = $464,869 )
2016	2016	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	8/1/2016	NEW	$464,869
														Subtotal = $464,869

Grand Total All Awards = $3,671,010

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Mechanistic details of key integral membrane enzymes for antimicrobial discovery

Award Number: R01GM114611

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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