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Imaging mass spectrometry and genome mining via short sequence tagging identified the anti-infective agent arylomycin in Streptomyces roseosporus.

ABSTRACT: Here, we described the discovery of anti-infective agent arylomycin and its biosynthetic gene cluster in an industrial daptomycin producing strain Streptomyces roseosporus. This was accomplished via the use of MALDI imaging mass spectrometry (IMS) along with peptidogenomic approach in which we have expanded to short sequence tagging (SST) described herein. Using IMS, we observed that prior to the production of daptomycin, a cluster of ions (1-3) was produced by S. roseosporus and correlated well with the decreased staphylococcal cell growth. With a further adopted SST peptidogenomics approach, which relies on the generation of sequence tags from tandem mass spectrometric data and query against genomes to identify the biosynthetic genes, we were able to identify these three molecules (1-3) to arylomycins, a class of broad-spectrum antibiotics that target type I signal peptidase. The gene cluster was then identified. This highlights the strength of IMS and MS guided genome mining approaches in effectively bridging the gap between phenotypes, chemotypes, and genotypes.

SUBMITTER: Liu WT

PROVIDER: S-EPMC3251218 | biostudies-literature | 2011 Nov

REPOSITORIES: biostudies-literature

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Imaging mass spectrometry and genome mining via short sequence tagging identified the anti-infective agent arylomycin in Streptomyces roseosporus.

Liu Wei-Ting WT Kersten Roland D RD Yang Yu-Liang YL Moore Bradley S BS Dorrestein Pieter C PC

Journal of the American Chemical Society 20111024 45

Here, we described the discovery of anti-infective agent arylomycin and its biosynthetic gene cluster in an industrial daptomycin producing strain Streptomyces roseosporus. This was accomplished via the use of MALDI imaging mass spectrometry (IMS) along with peptidogenomic approach in which we have expanded to short sequence tagging (SST) described herein. Using IMS, we observed that prior to the production of daptomycin, a cluster of ions (1-3) was produced by S. roseosporus and correlated well ...[more]

PMID: 21999343

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Project description:BackgroundUridyl 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.ResultsIn 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, 1'-6') 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 (3', 4', 5') 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.ConclusionsOverall, 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.

Dataset Information

Imaging mass spectrometry and genome mining via short sequence tagging identified the anti-infective agent arylomycin in Streptomyces roseosporus.

Publications

Imaging mass spectrometry and genome mining via short sequence tagging identified the anti-infective agent arylomycin in Streptomyces roseosporus.

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