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Methylotrophs: underexplored bacteria for discovering novel natural products and biochemistry

Award Number: R35GM147018
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: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Methylotrophs: underexplored bacteria for discovering novel natural products and biochemistry - PROJECT SUMMARY Natural products (NPs) and their derivatives are one of our main sources of therapeutics, due to the millennia these compounds have had to evolve interactions with their biological targets. However, the discovery of novel NPs from traditional sources has waned in recent decades, while at the same time we are facing mounting threats to human health such as increased antibiotic resistance. We therefore need new sources of NPs. One underexplored source of NPs is methylotrophs; bacteria that grow on reduced carbon compounds lacking carbon-carbon bonds such as methane gas. These organisms were overlooked during past NP discovery efforts due to their growth requirements, but genomic analysis demonstrates that they have significant potential to make novel NP scaffolds. I have been working with methylotrophs for close to a decade during my postdoctoral and independent research, and during that time I have developed genetic and metabolomic tools for these organisms. We are now ready to apply these tools to discover new methylotroph NPs with therapeutic value, as well as new enzymatic transformations that are involved in NP biosynthesis. Our research program is divided into two main directions. First, we will use our collection of ~100 unique bacterial strains isolated from methane enrichments to discover new therapeutically relevant leads. We are constructing a fraction library from this strain collection for use in bioactivity-based screens for antibiotic and anticancer compounds. Based on our findings, we will prioritize hits and perform advanced testing on these compounds with the help of our collaborators and supporting core centers. Because these strains almost all have sequenced genomes, we are also using similarity networking approaches and our genetic tools to identify and activate biosynthetic gene clusters that are likely to produce novel NPs. In our second research direction, we are capitalizing on our lab’s recently reported inverse stable isotopic labeling approach to identify methylotroph NPs that incorporate a known precursor. With this approach we will discover new NP scaffolds and associated novel biochemical transformations, and characterize these transformations both in vitro as well as in vivo in the native NP producing organisms. For both research directions, we have significant preliminary results that serve as examples of the types of projects that are developing within our research program. This work will identify new therapeutic leads with antibiotic and anticancer potential, and will also vet methods for prioritizing and activating the production of NPs from these underexplored bacteria. It will also address knowledge gaps in the biosynthesis of important NP classes (ribosomally synthesized and post-translationally modified peptides as well as enediynes), and characterize new enzymatic transformations that can be used as biocatalysts in medicinal chemistry efforts.


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 = $385,000 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	000	4	6/16/2025	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2024 ( Subtotal = $385,000 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	000	3	6/4/2024	NON-COMPETING CONTINUATION	$385,000
														Subtotal = $385,000

Issue Date FY: 2023 ( Subtotal = $394,978 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	001	2	6/19/2023	NON-COMPETING CONTINUATION	$385,000
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	000	1	5/10/2023	SUPPLEMENT FOR EXPANSION	$9,978
														Subtotal = $394,978

Issue Date FY: 2022 ( Subtotal = $383,750 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Biomedical Research and Research Training	000	1	6/20/2022	NEW	$383,750
														Subtotal = $383,750

Grand Total All Awards = $1,548,728

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Methylotrophs: underexplored bacteria for discovering novel natural products and biochemistry

Award Number: R35GM147018

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: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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