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Understanding metabolic and regulatory control of antibiotic production in filamentous actinobacteria

Award Number: R35GM158225
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: 08/05/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2030

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Understanding metabolic and regulatory control of antibiotic production in filamentous actinobacteria - Project Summary Bioactive molecules from nature are valuable templates for essential medicines. Filamentous actinobacteria are gifted producers of such molecules and rank among the richest sources yet discovered. They produce >50% of clinical antibiotics, plus numerous other medicines including immunotherapeutics and anticancer agents. These organisms dedicate a substantial fraction of their genomes to gene clusters predicted to encode drug-like compounds. Our research centers on a critical question: Why do the vast majority of actinobacterial biosynthetic gene clusters fail to yield anticipated products? There is an urgent need for new drug scaffolds and this problem transects multiple therapeutic areas. Gaining access to the plethora of yet-undiscovered drug-like molecules encoded within actinobacterial genomes could broadly revolutionize medicinal discovery and development. Coaxing actinobacteria to “turn-on” quiescent pathways is a challenge whose solution is fundamentally rooted in microbial physiology. Building on methodology and research insights established in our prior works, we here outline a multidisciplinary program that investigates two families of antibiotic molecules as models to reveal new mechanisms controlling production phenotypes. These molecules, polycyclic tetramate macrolactams and piperazyl-peptides, are broadly distributed among filamentous actinomycetes. They are largely chemically and biosynthetically distinct but share a common link via ornithine metabolism. Goal 1) Our prior works establish small nucleotide changes in transcriptional promoters can “tune” antibiotic production. How do these promoter polymorphisms exert their control? How can this knowledge be applied to override poor production traits? Goal 2) Certain piperazyl pathways respond positively to ornithine and related pathway intermediates. This suggests a mechanism of metabolic control. We ask: Because both types of antibiotics we study require ornithine precursors, might cellular ornithine status constitute an important regulatory component that could empower discovery strategies for both? Goal 3) We recently established a positive relationship between cellular growth on solid surfaces and polycyclic tetramate macrolactam production in certain strains. We hypothesize this intriguing relationship may extend to other antibiotic production pathways as well. We ask: How do actinobacterial surface interactions modulate bioactive molecule production, and might answering this deliver novel insights for broad-scale biosynthetic activation?


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 = $416,050 )
2025	2025	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Biomedical Research and Research Training	000	1	8/4/2025	NEW	$416,050
														Subtotal = $416,050

Grand Total All Awards = $416,050

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Understanding metabolic and regulatory control of antibiotic production in filamentous actinobacteria

Award Number: R35GM158225

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: 08/05/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2030

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