Microbial quorum sensing signaling molecules and their roles in the biosynthesis of natural products

Zhang, Jihui; Tan, Huarong

doi:10.1007/s11427-023-2389-7

Cited by 2 publications

(1 citation statement)

References 15 publications

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“…The discovery of potential drug leads from microbial resources has been well accepted as a way to fight against antibiotic-resistant pathogens. With the advancement of multiple disciplinary technologies, efficient strategies are emerging for activating and rational engineering the biosynthetic pathways of natural products, including genome mining, regulatory gene manipulation, signaling modulation, metabolic flux maneuver and synthetic biology, which have accelerated the enrichment of natural products [ 1 – 3 ].…”

Section: Introductionmentioning

confidence: 99%

New insights into the dihydro-mureidomycin biosynthesis controlled by two unusual proteins in Streptomyces roseosporus

Liu,

Xu,

Shang

et al. 2023

Microb Cell Fact

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Background Uridyl peptide compounds are renowned as a subclass of nucleoside antibiotics for their highly specific antibacterial activity against Gram-negative bacteria and the unique target of action. We previously activated the biosynthetic gene cluster of a uridyl peptide antibiotic, mureidomycin, in Streptomyces roseosporus NRRL 15998 by introducing an exogenous positive regulator gene ssaA, and the generated strain was designated as Sr-hA. This study aims to further explore mureidomycin analogs from Sr-hA as well as the collaborative roles of two wide-spread genes, SSGG-02980 and SSGG-03002 encoding putative nuclease/phosphatase and oxidoreductase respectively, in mureidomycin diversification. Results In order to understand how SSGG-02980 and SSGG-03002 contribute to mureidomycin biosynthesis, the gene disruption mutants and complementary strains were constructed. Mass spectrometry analyses revealed that two series of pairwise mureidomycin analogs were synthesized in Sr-hA with a two-dalton difference in molecular weight for each pair. By disruption of SSGG-03002, only mureidomycins with lower molecular weight (MRDs, 1–6) could be specifically accumulated in the mutant (∆03002-hA), whereas the other series of products with molecular weight plus 2 Da (rMRDs, 1ʹ–6ʹ) became dominant in SSGG-02980 disruption mutant (∆02980-hA). Further comprehensive NMR analyses were performed to elucidate the structures, and three MRDs (3, 4, 5) with unsaturated double bond at C5-C6 of uracil group were characterized from ∆03002-hA. In contrast, the paired rMRDs analogs (3ʹ, 4ʹ, 5ʹ) from ∆SSGG-02980 corresponding to 3, 4 and 5 were shown to contain a single bond at this position. The results verified that SSGG-03002 participates in the reduction of uracil ring, whereas SSGG-02980 antagonizes the effect of SSGG-03002, which has been rarely recognized for a phosphatase. Conclusions Overall, this study revealed the key roles of two wide-spread families of enzymes in Streptomyces. Of them, oxidoreductase, SSGG-03002, is involved in dihydro-mureidomycin biosynthesis of S. roseosporus, whereas nuclease/phosphatase, SSGG-02980, has an adverse effect on SSGG-03002. This kind of unusual regulation model between nuclease/phosphatase and oxidoreductase is unprecedented, providing new insights into the biosynthesis of mureidomycins in Streptomyces. The findings would be of significance for structural diversification of more uridyl peptide antibiotics against Gram-negative bacteria.

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Section: Introductionmentioning

confidence: 99%

New insights into the dihydro-mureidomycin biosynthesis controlled by two unusual proteins in Streptomyces roseosporus

Liu,

Xu,

Shang

et al. 2023

Microb Cell Fact

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Omics-assisted systematic exploration of the intricate regulatory network of guvermectin biosynthesis centered by the cluster-situated regulator GvmR inStreptomyces

Shi,

Wang,

et al. 2023

Preprint

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Guvermectin, produced byStreptomycesbacteria, is a purine nucleoside natural product recently registered as a new biopesticide to boost rice yield. Despite its importance, the regulatory network governing guvermectin biosynthesis remains largely unknown, severely impeding industrial-scale production and widespread application in rice production. Here, we investigated the diverse regulatory mechanisms employed by the cluster-situated regulatory gene,gvmR, in controlling guvermectin production from the perspective of widespread disturbance of gene expression at genome scale. GvmR activates the expression of guvermectin cluster by binding to thegvmR,gvmAandO1promoters. Additionally, GvmR binds to the promoter ofscnR1, a previously unidentified and highly conserved regulator inStreptomyces.scnR1overexpression significantly suppressed guvermectin production by regulating the guvermectin cluster through binding to the same promoters as GvmR. Transcriptomic analysis revealed that GvmR extensively influences the expression of numerous genes located outside the guvermectin cluster, including the precursor supply (purine biosynthesis) and energy synthesis (oxidative phosphorylation) pathway genes, as well as 252 transcriptional regulatory genes. By genetic screening from 48 of these 252 regulatory genes, we identified additional five highly conserved genes that impact guvermectin production, suggesting a functional interplay between GvmR and highly conserved regulators in coordinating guvermectin production. These findings enrich our knowledge of the regulatory network governing guvermectin biosynthesis and offer a broadly applicable approach for investigating the molecular regulation of natural product biosynthesis and their high-titer production.

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Microbial quorum sensing signaling molecules and their roles in the biosynthesis of natural products

Cited by 2 publications

References 15 publications

New insights into the dihydro-mureidomycin biosynthesis controlled by two unusual proteins in Streptomyces roseosporus

New insights into the dihydro-mureidomycin biosynthesis controlled by two unusual proteins in Streptomyces roseosporus

Omics-assisted systematic exploration of the intricate regulatory network of guvermectin biosynthesis centered by the cluster-situated regulator GvmR inStreptomyces

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