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Redefining Fermentation Parameters in Natural Products Drug Discovery

Award Number: R16AI167814
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/23/2022
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Redefining Fermentation Parameters in Natural Products Drug Discovery - PROJECT SUMMARY The discovery of antibiotics from soil microbes is widely regarded as one of the most significant achievements in modern medicine, enabling many important medical procedures including surgery and cancer chemotherapy. However, antibiotic resistance is approaching such a critical level that we are facing an eminent public health disaster where many significant medical advancements may no longer be possible. There is an urgent need to develop and/or discover novel classes of antibiotics, especially antibiotics that are active against high-priority Gram-negative pathogens. Natural products have served as the scaffold for the vast majority of our current antibiotics, and recent advances in genomics, metagenomics, and metabolomics clearly indicate that there is still a vast wealth of biosynthetic potential encoded in bacterial genomes that could produce novel antibiotics. Unfortunately, identifying a novel biosynthetic gene clusters (BGCs) in a genome provides us with very little information about the chemical nature of the natural product it might produce. Thus, the field of natural product discovery, and consequently the field of antibiotic discovery, faces two major obstacles: how do we quickly and efficiently identify strains that have the potential to produce desirable novel compounds from “silent” BGCs and then how do we consistently induce the expression of these BGCs to characterize the compounds they produce. The induction of silent BGCs that produce antibiotics is likely context or community dependent, especially given the self-harming effects of antimicrobial compounds. Our previous work has validated a method for identifying microbes that produce antimicrobial compounds from silent BGCs, and this proposal describes methods for optimizing single- and mixed-culture fermentation conditions to consistently produce these compounds. In the research aims, we propose two complementary approaches to develop reproducible and scalable fermentation conditions that can broadly stimulate silent antibiotic production, which is often a rate limiting step in the field of natural products chemistry. Aim 1 will expand on our observations that microbes increase the production of antimicrobial compounds when grown in otherwise nutrient-limited media where complex polysaccharides are their dominant carbon source. Aim 2 will use co-culture to manipulate microbial physiological prior to fermentation. We expect that our optimized culture conditions will enable us to obtain natural product extracts that contain sufficient compound for feature-based molecular networking (FBMN) analyses to dereplicate antimicrobial compounds prior to activity-guided purification and structural elucidation of bioactive compounds (Aim 3).


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 = $150,000 )
2025	2025	EASTERN MICHIGAN UNIVERSITY	203 PIERCE HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	4	8/1/2025	NON-COMPETING CONTINUATION	$150,000
														Subtotal = $150,000

Issue Date FY: 2024 ( Subtotal = $150,000 )
2024	2024	EASTERN MICHIGAN UNIVERSITY	203 PIERCE HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Allergy and Infectious Diseases Research	001	3	9/10/2024	NON-COMPETING CONTINUATION	$0
2024	2024	EASTERN MICHIGAN UNIVERSITY	203 PIERCE HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	3	6/27/2024	NON-COMPETING CONTINUATION	$150,000
														Subtotal = $150,000

Issue Date FY: 2023 ( Subtotal = $150,000 )
2023	2023	EASTERN MICHIGAN UNIVERSITY	202 WELCH HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Allergy and Infectious Diseases Research	001	2	8/17/2023	NON-COMPETING CONTINUATION	$150,000
2023	2022	EASTERN MICHIGAN UNIVERSITY	202 WELCH HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	8/16/2023	NEW	$0
														Subtotal = $150,000

Issue Date FY: 2022 ( Subtotal = $162,125 )
2022	2022	EASTERN MICHIGAN UNIVERSITY	202 WELCH HALL	YPSILANTI	MI	48197	WASHTENAW	USA	Allergy and Infectious Diseases Research	000	1	8/23/2022	NEW	$162,125
														Subtotal = $162,125

Grand Total All Awards = $612,125

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Redefining Fermentation Parameters in Natural Products Drug Discovery

Award Number: R16AI167814

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/23/2022

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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