Understanding metabolic and regulatory control of antibiotic production in filamentous actinobacteria
Active Project Grant Awarded Last action
- Award ID
- R35GM158225
- Recipient
-
The Washington University UEI L6NFUM28LQM5
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $804,800
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 25% complete
- Place of performance
- University City, MO 63130, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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?
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $388,750 | |
| Original award | $416,050 |
Quick answers
Who received award R35GM158225?
R35GM158225 was awarded to The Washington University by National Institute of General Medical Sciences (National Institutes of Health) on August 5, 2025.
How much is award R35GM158225 worth?
$804,800 has been obligated on R35GM158225.
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