Thursday, November 21, 2024 11/21/2024

Accessing and expanding microbial bioactive chemical diversity by synthetic biology and new enzymology

Award Number: R35GM128742
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Natural products (NPs) form a validated and preeminent source of new drug leads, but the low rate of new discoveries and the limited access to bioactive compounds are challenging current NPs-based drug discovery and development. Over the past decades, genome mining has become an important way for NP discovery. This transformative research strategy combines functional genomics and bioinformatics to associate biosynthetic gene clusters (BGCs) with potential chemical entities. The success of this strategy is supported by increasing and rapid access to (meta)genomic data, from which diverse rule-based and -free bioinformatics tools enable depicting the BGCs of different compound families and even assessing their novelty and potential bioactivity. However, a fundamental challenge faced by genome mining research is how to produce sufficient amounts of novel, bioactive NPs from mined BGCs. The overall goal of the PI's research program is to access and expand the therapeutically relevant chemical diversity of microbes directly from their genomes. The central hypothesis of this work is that microbial genomes can be exploited to produce bioactive NPs and analogs through synthetic biology (SynBio) and enzymology research. SynBio has achieved many notable successes in the production of bioactive compounds over the past two decades. In the NP discovery, SynBio studies can allow the expression of natural and designed BGCs in capable chasses. In parallel, the biosynthesis of microbial NPs is enriched with functionally diverse enzymes that lend enabling strategies to produce key intermediates and analogs of bioactive NPs. To achieve the goal and test the hypothesis, this renewal will pursue two interlinked research directions. Direction 1 will focus on the discovery and production of bioactive NPs from less-explored resources, particularly in marine entrainment. To maximize the success, our SynBio research will develop and use chasses of multiple bacterial phyla. Research direction 2 of this proposal will discover and characterize synthetically significant enzymes using a diverse set of approaches, aiding the access and expansion of therapeutically relevant chemical diversity of NPs. New enzymes found in Direction 1 will be characterized in Direction 2 and can then support the mining of new BGCs in Direction 1, leading to tight integration and mutual support of the two directions. Together, these two directions can afford innovative strategies that enable the effective exploitation of bioactive NPs from the genomes of less-studied microbes. These studies can also boost the transformation of NP research from small-scale pursuits to a genome-based high-throughput endeavor, therefore supporting the paradigm shift in NP-based drug research.


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 = $0 )
2025	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	7	11/6/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $363,524 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	7	6/18/2024	NON-COMPETING CONTINUATION	$363,524
														Subtotal = $363,524

Issue Date FY: 2023 ( Subtotal = $386,145 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	6	5/16/2023	COMPETING CONTINUATION	$386,145
														Subtotal = $386,145

Issue Date FY: 2022 ( Subtotal = $467,766 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	5	7/14/2022	NON-COMPETING CONTINUATION	$350,270
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	4	5/23/2022	SUPPLEMENT FOR EXPANSION	$117,496
														Subtotal = $467,766

Issue Date FY: 2021 ( Subtotal = $346,488 )
2021	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	4	8/11/2021	NON-COMPETING CONTINUATION	$346,488
														Subtotal = $346,488

Issue Date FY: 2020 ( Subtotal = $342,884 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	3	6/11/2020	NON-COMPETING CONTINUATION	$342,884
														Subtotal = $342,884

Issue Date FY: 2019 ( Subtotal = $427,512 )
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	2	8/7/2019	SUPPLEMENT FOR EXPANSION	$70,059
2019	2019	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	2	5/31/2019	NON-COMPETING CONTINUATION	$357,453
														Subtotal = $427,512

Issue Date FY: 2018 ( Subtotal = $356,478 )
2018	2018	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	000	1	6/29/2018	NEW	$356,478
														Subtotal = $356,478

Grand Total All Awards = $2,690,797

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Accessing and expanding microbial bioactive chemical diversity by synthetic biology and new enzymology

Award Number: R35GM128742

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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