Activation of Cryptic Antibiotic Biosynthetic Gene Clusters Guided by RNA-seq Data from Both Streptomyces ansochromogenes and ΔwblA

Li, Yue; Yu, Haiying; Guan, Hanye; Li, Jingjing; Zhang, Jihui; Xiang, Hua; Li, Jine; Tan, Huarong

doi:10.3390/antibiotics10091097

Cited by 8 publications

(5 citation statements)

References 41 publications

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“…The corresponding BGC was identified (Fig. 3a ), and renamed as ang in this study for its high identity with angolamycin BGC 39 , 40 . To demonstrate if VRS-bAHL can facilitate the characterization of the activated secondary metabolite BGCs, an ang expression reporter strain 7100ang-cviI was constructed, in which P ang1 , the promoter of a key structural gene ang1 (also named as ctg1_1275 ), was used to drive cviI .…”

Section: Resultsmentioning

confidence: 99%

A visualization reporter system for characterizing antibiotic biosynthetic gene clusters expression with high-sensitivity

Liu

et al. 2022

Commun Biol

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The crisis of antibiotic resistance has become an impending global problem. Genome sequencing reveals that streptomycetes have the potential to produce many more bioactive compounds that may combat the emerging pathogens. The existing challenge is to devise sensitive reporter systems for mining valuable antibiotics. Here, we report a visualization reporter system based on Gram-negative bacterial acyl-homoserine lactone quorum-sensing (VRS-bAHL). AHL synthase gene (cviI) of Chromobacterium violaceum as reporter gene is expressed in Gram-positive Streptomyces to synthesize AHL, which is detected with CV026, an AHL deficient mutant of C. violaceum, via its violacein production upon AHL induction. Validation assays prove that VRS-bAHL can be widely used for characterizing gene expression in Streptomyces. With the guidance of VRS-bAHL, a novel oxazolomycin derivative is discovered to the best of our knowledge. The results demonstrate that VRS-bAHL is a powerful tool for advancing genetic regulation studies and discovering valuable active metabolites in microorganisms.

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Section: Resultsmentioning

confidence: 99%

A visualization reporter system for characterizing antibiotic biosynthetic gene clusters expression with high-sensitivity

Liu

et al. 2022

Commun Biol

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“…There is an urgent need to cope with the antibiotic crisis and resistant pathogens, especially those with cross-resistance to multiple drugs. Mining of genomes with multi-omics techniques and rational modification of compounds are quick approaches for expanding the capacity of bioactive products libraries [ 20 ]. Uridyl peptide compounds are emerging as a new family of drug leads for their unique activities specifically against the Gram-negative bacteria Pseudomonas ; hence, they hold great potential in clinical applications.…”

Section: Discussionmentioning

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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“…3A). 32 The comparative analysis of RNA-seq data revealed that the disruption of wblA abolished the biosynthesis of nikkomycin, acarbose, and validamycin while activating the biosynthesis of tylosin analog, porphyrin, and chlorophyll. The RNA-seq data also identified that the regulatory gene rsbR is positively regulated by WblA.…”

Section: Transcriptional Analysis Of Natural Product Biosynthetic Gen...mentioning

confidence: 99%

Promoter engineering of natural product biosynthetic gene clusters in actinomycetes: concepts and applications

Ji,

Je,

Kim

et al. 2024

Nat. Prod. Rep.

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Activation of Cryptic Antibiotic Biosynthetic Gene Clusters Guided by RNA-seq Data from Both Streptomyces ansochromogenes and ΔwblA

Cited by 8 publications

References 41 publications

A visualization reporter system for characterizing antibiotic biosynthetic gene clusters expression with high-sensitivity

A visualization reporter system for characterizing antibiotic biosynthetic gene clusters expression with high-sensitivity

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

Promoter engineering of natural product biosynthetic gene clusters in actinomycetes: concepts and applications

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