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Genetic and structural analysis of L,L-diaminopimelate aminotransferase (DapL): An attractive target for the development of narrow-spectrum antibiotics

Award Number: R15GM120653
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: 09/06/2016
PERIOD OF PERFORMANCE END DATE: 12/31/2020

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Genetic and structural analysis of L,L-diaminopimelate aminotransferase (DapL): An attractive target for the development of narrow-spectrum antibiotics - PROJECT SUMMARY/ABSTRACT The overarching goal of this proposal is to assess the essentiality of L,L-diaminopimelate aminotransferase in pathogenic bacteria to facilitate the development of antibiotics. There is an urgent need for the development of novel antibiotics to combat the drastic rise in the number of antibiotic resistant bacteria. One of the bottlenecks that is impeding the development of antibiotics is the identification of novel enzymatic targets. The PI recently identified and elucidated a novel variant of the diaminopimelate/lysine biosynthesis pathway by identifying and characterizing the enzyme L,L-diaminopimelate aminotransferase. In pathogenic bacteria, such as Chlamydia trachomatis, diaminopimelate aminotransferase catalyzes a specific reaction in the diaminopimelate/lysine anabolic pathway that is necessary for both cell wall peptidoglycan and amino acid protein synthesis. The genomes of animals, particularly humans, do not contain the genetic machinery necessary to facilitate the synthesis of diaminopimelate/lysine. As such, the enzymes in this pathway are attractive targets for novel antibiotics. We hypothesize that inhibition of diaminopimelate aminotransferase in the pathogenic bacteria will cause a bactericidal effect through inhibition of peptidoglycan synthesis and protein synthesis. This is because 1) the intermediate meso-diaminopimelate/lysine serves a cross-linking amino acid in the peptidoglycan of bacteria and 2) lysine is one of the 20 common proteogenic amino acids. The proposed research is significant since we will assess the essentiality of the dapL gene in the Gram- negative bacterium Verrucomicrobium spinosum, the closest free living relative of Chlamydia, the causative bacterium in the sexually transmitted disease “Chlamydia”. V. spinosum was chosen as a model because it employs the diaminopimelate aminotransferase pathway as the sole pathway for peptidoglycan and lysine biosynthesis. The organism is not pathogenic and it can be genetically manipulated. To test if diaminopimelate aminotransferase is a feasible target for the development of novel antibiotics we have delineated three aims. 1) We will assess the essentiality of diaminopimelate aminotransferase in eubacteria using the V. spinosum as a model using mutagenesis experiments employing transposon and/or gene replacement of the dapL gene. 2) Recent studies from PI’s lab have identified antagonistic lead compounds towards diaminopimelate aminotransferase using in vitro assays. As such, we will discern the specificity of these compounds using a in vivo system where we will use V. spinosum wild type and diaminopimelate aminotransferase mutants to assess if these identified compounds are specific for diaminopimelate aminotransferase and 3) The final aim of the project will identify the amino acids that are involved in the binding of antagonistic compounds by incubating the enzyme with these compounds followed by structural analyses facilitated by X-ray crystallography, which will underpin the development of second generation 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: 2022 ( Subtotal = $0 )
2022	2017	ROCHESTER INSTITUTE OF TECHNOLOGY (INC)	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	001	1	9/26/2022	SUPPLEMENT FOR EXPANSION	$1,253
2022	2017	ROCHESTER INSTITUTE OF TECHNOLOGY (INC)	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	1	3/2/2022	SUPPLEMENT FOR EXPANSION	-$1,253
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = -$6,335 )
2021	2017	ROCHESTER INSTITUTE OF TECHNOLOGY (INC)	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	1	5/30/2021	SUPPLEMENT FOR EXPANSION	-$6,335
														Subtotal = -$6,335

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	ROCHESTER INSTITUTE OF TECHNOLOGY (INC)	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	001	1	7/23/2020	SUPPLEMENT FOR EXPANSION	$0
2020	2016	ROCHESTER INSTITUTE OF TECHNOLOGY (INC)	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	1	7/23/2020	NEW	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $30,765 )
2017	2017	ROCHESTER INSTITUTE OF TECHNOLOGY (INC)	1 LOMB MEMORIAL DR	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	1	8/31/2017	SUPPLEMENT FOR EXPANSION	$30,765
														Subtotal = $30,765

Issue Date FY: 2016 ( Subtotal = $436,989 )
2016	2016	ROCHESTER INSTITUTE OF TECHNOLOGY	ONE LOMB MEMORIAL DRIVE	ROCHESTER	NY	14623	MONROE	USA	Biomedical Research and Research Training	000	1	9/5/2016	NEW	$436,989
														Subtotal = $436,989

Grand Total All Awards = $461,419

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Genetic and structural analysis of L,L-diaminopimelate aminotransferase (DapL): An attractive target for the development of narrow-spectrum antibiotics

Award Number: R15GM120653

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: 09/06/2016

PERIOD OF PERFORMANCE END DATE: 12/31/2020

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