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Desferrioxamine siderophores are assembled by the nonribosomal-peptide-synthetase-independent-siderophore (NIS) synthetase enzyme DesD via ATP-dependent iterative condensation of three N1-hydroxy-N1-succinyl-cadaverine (HSC) units. Current knowledge of NIS enzymology and the desferrioxamine bio-synthetic pathway does not account for the existence of most known members of this natural product family which differ in substitution patterns of the N- and C-termini. The directionality of desferrioxamine biosyn-thetic assembly, N-to-C vs C-to-N, is a longstanding knowledge gap that is limiting further progress in un-derstanding the origins of natural products in this structural family. Here, we establish the directionality of desferrioxamine biosynthesis using a chemoenzymatic approach with stable isotope incorporation and di-meric substrates. We propose a mechanism where DesD catalyzes the N-to-C condensation of HSC units to establish a unifying biosynthetic paradigm for desferrioxamine natural products in Streptomyces.
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This content will become publicly available on December 1, 2027
Multi-omics analysis of interspecies interactions in a soil Streptomyces community provides functional insights into siderophore ecology
Abstract Streptomycesare key contributors to soil microbiome function, known for their biosynthetic diversity. While advances in -omics technologies have improved our understanding of microbiome composition and metabolic potential, the mechanisms underpinning interspecies interactions remain poorly resolved. Here, we investigate the molecular basis of interactions among four sympatricStreptomycessoil microbiome isolates, focusing on phenotypic, metabolomic and transcriptomic responses. Co-culture experiments revealed that one isolate, strain A, exhibited pronounced phenotypic changes when grown alongside each of the other three strains. Untargeted metabolomics and RNA-seq analyses showed that strain A undergoes distinct metabolic and transcriptional shifts depending on its partner, with the strongest response elicited by strain C. Despite all four strains possessing a conserved desferrioxamine biosynthetic gene cluster, only strain C constitutively produced desferrioxamine B (DFO-B), a hydroxamate siderophore, indicating a role for iron bioavailability in the interaction. Supplementation with DFO-B or iron mimicked the growth stimulation of strain A observed in co-culture with strain C, and CRISPR base editing ofdesDin strain C abolished both DFO production and the phenotypic induction of strain A. However, transcriptomic profiles of strain A varied significantly depending on the partner strain, with distinct sets of biosynthetic gene clusters and metabolic pathways activated in response to strains B and C, suggesting additional cues beyond DFO-B. In contrast, strain D did not elicit growth stimulation in its partners, and itself showed downregulation of amino acid and carbon metabolism when co-cultured with strain C. These findings indicate thatStreptomycesinteractions are not only mediated by siderophore piracy but also involve complex, strain-specific molecular responses. Our findings demonstrate thatStreptomycesinteractions are highly strain-specific and only partly mediated by siderophore piracy, with DFO-B acting as a potent interspecies cue. The divergent molecular responses to different partners suggest nuanced mechanisms of microbial sensing and competition. These insights advance our understanding of microbial crosstalk and highlight the ecological and evolutionary complexity of siderophore-mediated interactions. By integrating transcriptomics, metabolomics, and biochemical assays, we present a robust framework for dissecting microbial interactions, with implications for microbiome engineering and synthetic community design.
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- Award ID(s):
- 2425352
- PAR ID:
- 10686800
- Publisher / Repository:
- Nature Portfolio
- Date Published:
- Journal Name:
- Scientific Reports
- Volume:
- 16
- Issue:
- 1
- ISSN:
- 2045-2322
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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