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Mining Cryptic Biosynthetic Gene Clusters for Novel Bioactive Compounds and Biocatalysts

Award Number: R35GM138002
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: 07/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Mining Cryptic Biosynthetic Gene Clusters for Novel Bioactive Compounds and Biocatalysts - PROJECT SUMMARY/ABSTRACT Natural products from the soil-dwelling bacteria Streptomyces have been a rich source of medicines. Additionally, the enzymes that produce natural products perform unique and challenging chemistry, providing inspiration for novel biocatalysts. One important class of natural products is cyclic nonribosomal peptides. Unfortunately, the discovery of novel cyclic peptides using traditional techniques is often unsuccessful. Also, chemical synthesis of cyclic peptides, especially small strained tetrapeptides, remains a challenge, resulting them being underexplored as potential therapeutics. Genomics data suggests a plethora of novel Streptomyces cyclic peptides and their biosynthetic enzymes remain to be discovered. However, the biosynthetic machinery responsible for producing these novel natural products is often cryptic (i.e. transcriptionally inactive). A significant gap remains in the strategies available to discover new bioactive cyclic peptide natural products and to synthesize these peptides, especially cyclic tetrapeptides, for further analysis. Our long-term goals are to 1) Discover biosynthetic enzymes that perform unique and challenging reactions and develop these enzymes as biocatalysts, and 2) Develop bioinformatics and synthetic techniques that allow us to directly access natural products from cryptic biosynthetic gene clusters. Our current research objectives are to 1) Determine activities and substrate scopes for previously identified, as well as bioinformatically predicted, tetrapeptide cyclases and develop the most promising ones as biocatalysts and 2) Utilize bioinformatics methods to identify nonribosomal peptides of interest followed by direct chemical synthesis and biological testing to identify bioactive leads. Our recent discovery of the first standalone tetrapeptide cyclase and our development of the Synthetic Natural Product Inspired Cyclic Peptide (SNaPP) methodology, make us well positioned to complete these objectives. The central hypothesis of the first project is natural product biosynthetic enzymes will be efficient biocatalysts for the generation of cyclic tetrapeptides that otherwise are very challenging to access. The objectives of the first project are to 1) better understand the mechanism of Ulm16, a known tetrapeptide cyclase 2) bioinformatically identify new tetrapeptide cyclases and 3) apply these tetrapeptide cyclases to the synthesis of bioactive cyclic tetrapeptides and the development of cyclic tetrapeptide libraries for screening. In the second project, we are directly chemically synthesizing natural products that are bioinformatically predicted from nonribosomal peptide synthetase biosynthetic gene clusters. While our previous work in this area has resulted in promising bioactive leads, challenges remain including accurate predictions of off-loading methods, unnatural amino acids, and tailoring enzymes. The objectives for the second project are to address these challenges by incorporating predictions of these three areas into our predicted peptides and then synthesizing them. This work will provide access to many novel natural product scaffolds that are currently inaccessible and that are likely to have interesting bioactivities.


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 = $544,123 )
2025	2025	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Biomedical Research and Research Training	000	6	5/27/2025	COMPETING CONTINUATION	$544,123
														Subtotal = $544,123

Issue Date FY: 2024 ( Subtotal = $370,472 )
2024	2024	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Biomedical Research and Research Training	000	5	6/12/2024	NON-COMPETING CONTINUATION	$370,472
														Subtotal = $370,472

Issue Date FY: 2023 ( Subtotal = $370,472 )
2023	2023	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Biomedical Research and Research Training	000	4	4/28/2023	NON-COMPETING CONTINUATION	$370,472
														Subtotal = $370,472

Issue Date FY: 2022 ( Subtotal = $370,472 )
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Biomedical Research and Research Training	000	3	5/9/2022	NON-COMPETING CONTINUATION	$370,472
														Subtotal = $370,472

Issue Date FY: 2021 ( Subtotal = $470,688 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Biomedical Research and Research Training	002	2	7/26/2021	SUPPLEMENT FOR EXPANSION	$100,216
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Biomedical Research and Research Training	001	2	4/26/2021	NON-COMPETING CONTINUATION	$370,472
2021	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Biomedical Research and Research Training	000	1	3/9/2021	NEW	$0
														Subtotal = $470,688

Issue Date FY: 2020 ( Subtotal = $370,472 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Biomedical Research and Research Training	000	1	6/26/2020	NEW	$370,472
														Subtotal = $370,472

Grand Total All Awards = $2,496,699

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Mining Cryptic Biosynthetic Gene Clusters for Novel Bioactive Compounds and Biocatalysts

Award Number: R35GM138002

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: 07/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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