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Rao M.,Nanjing Agricultural University | Feng L.,Shanghai JiaoTong University | Ruan L.,Shanghai JiaoTong University | Ge M.,Shanghai Laiyi Center for Biopharmaceuticals RandD | And 2 more authors.
Analytical Letters | Year: 2013

The A21978C family of compounds includes precursors of daptomycin, an important antibiotic for the treatment of diseases infected by Gram-positive resistant bacteria. Focusing on these valuable compounds, the differences in metabolites obtained with or without pH control in their producing strain Streptomyces parvus HCCB10043 were investigated by comparative metabolomics analysis based on UPLC-TOF-MS technology. According to principal component analysis, there were fourteen biomarker compounds selected under the two pH culture conditions. The ten known compounds were divided into two types: a glycoside family participating in the primary metabolism (daidzein, glycitein, genistein, and soyasaponin Bb) and a peptide family of secondary metabolites (valistatin, bestatin, 3-amino-2-hydroxy-4-phenylbutanoylvalylisoleucine, and arylomycins A2, A4, and A5). Through orthogonal partial least squares-discriminant analysis, three compounds, soyasaponin Bb and arylomycins A2 and A4 were identified as the most relevant compounds to A21978C1-3 production, the glycolytic pathway, and the NRPS synthesis pathway. The competitive relationship between arylomycin and A21978C was verified. These results have demonstrated the usefulness of the metabolomic strategy based on UPLC-MS in studying significant metabolic changes in actinomycetes. Moreover, this metabolomic strategy can provide new ideas and guidance for the regulation and improvement of secondary metabolites production. © 2013 Copyright Taylor and Francis Group, LLC.


Rao M.,Nanjing Agricultural University | Rao M.,Shanghai Laiyi Center for Biopharmaceuticals RandD | Li Q.,Shanghai JiaoTong University | Feng L.,Shanghai JiaoTong University | And 5 more authors.
Analytical and Bioanalytical Chemistry | Year: 2011

The diversity of microbial metabolites has been of interest and concern for a long time, yet a suitable method for discovering these is still unavailable. In the work discussed in this report, ultra-performance liquid chromatography coupled with tandem quadrupole and time of flight high-resolution mass spectrometry (UPLC-Q-TOF-HRMS), with MS data analysis, was set up to study the metabolites of Streptomyces strain HCCB10043. It was found that besides antibacterial substances (A21978C complex) and two anti-aminopeptidase compounds (valistatin and bestatin), this strain can produce a new aminopeptidase inhibitor, identified as 3-amino-2-hydroxy-4-phenylbutanoylvalylisoleucine. This new compound had greater activity than valistatin or bestatin in aminopeptidase N (APN) inhibition assay. The results proved that combination of UPLC-Q-TOF-MS analysis and classic purification and identification steps as complementary strategies can provide a method with high reliability for research on microbial secondary metabolites. Furthermore, it has shown that the study of secondary metabolic profiling might be the key to discovering new drugs. [Figure not available: see fulltext.] © 2011 Springer-Verlag.


Rao M.,Nanjing Agricultural University | Wei W.,Shanghai Laiyi Center for Biopharmaceuticals RandD | Wei W.,Shanghai JiaoTong University | Ge M.,Shanghai Laiyi Center for Biopharmaceuticals RandD | And 3 more authors.
Natural Product Research | Year: 2013

It is an attractive and interesting thing for us to mine the diversity of microbial metabolites by means of ultra performance liquid chromatography tandem quadrupole and time of flight high-resolution mass spectrometry. Through this method, two trace compounds, a new lipopeptide, named arylomycin A6 (1), and a known lipopeptide (arylomycin A5, 2) were found and isolated from an actinomycete Streptomyces parvus HCCB10043. The structure of the new lipopeptide was elucidated by a combination of 1D, 2D NMR (correlation spectroscopy, heteronuclear multiple quantum correlation and heteronuclear multiple bond coherence) techniques, high-resolution electrospray ionization mass spectrometry and MS/MS spectrometry and fatty acid analyses. Arylomycin A6 exhibited antibacterial activity against Staphylococcus epidermidis HCCB20256 with the minimum inhibitory concentration of 1 g/mL. Till now, arylomycins are the third series of active secondary metabolites we found in S. parvus HCCB10043. The results strongly support and encourage the studies for mining trace natural active products from microorganisms like Streptomyces. © 2013 © 2013 Taylor & Francis.


Jin X.,Nanjing Agricultural University | Jin X.,Shanghai Laiyi Center for Biopharmaceuticals RandD | Rao M.,Nanjing Agricultural University | Rao M.,Shanghai Laiyi Center for Biopharmaceuticals RandD | And 8 more authors.
Biotechnology Letters | Year: 2012

Arylomycins are type I signal peptidase inhibitors and have a potential as a new type of antibiotics. They were identified from the broth of Streptomyces sp. HCCB10043. The arylomycin biosynthetic gene cluster in this strain was identical to that in S. roseosporus. Within the gene cluster, aryC, encoding a P450 enzyme, was deduced to be responsible for biaryl bond formation in, the arylomycins. Inactivation of aryC abolished arylomycin production and led to the generation of two novel linear lipopentapeptides lacking the aryl-aryl linkage. These derivatives had lost their antibacterial activities against Staphylococcus epidermidis which is sensitive to arylomycins A2 and A4. © 2012 Springer Science+Business Media B.V.

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