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    Online Resource
    Online Resource
    Rapid identification of atypical tetracyclines using tandem mass spectrometric fragmentation patterns
    Wiley ; 2015
    In:  Rapid Communications in Mass Spectrometry Vol. 29, No. 17 ( 2015-09-15), p. 1556-1562
    Details
    In: Rapid Communications in Mass Spectrometry, Wiley, Vol. 29, No. 17 ( 2015-09-15), p. 1556-1562
    Abstract: When applying biosynthetic engineering approaches at the early stages of drug discovery, e.g. aiming to develop novel tetracycline analogues, target compounds are generally produced by engineered microorganisms in low yields. Rapid and reliable identification of metabolites with desired structural modification directly from bacterial cultures is therefore of great importance. Methods Structural elucidation of atypical tetracyclines was carried out by fragmentation applying electrospray ionisation tandem mass spectrometry (ESI‐MS/MS) (triple quadrupole – linear ion trap; Applied Biosystems 4000 QTRAP) and a high‐resolution mass spectrometer (Agilent Technologies 6224 TOF). Fragmentation patterns were obtained either with direct injection or by applying separation of target compounds with high‐performance liquid chromatography (HPLC) prior to mass spectrometry. In‐source and CID fragmentation were compared. Theoretical calculations of target structures using the Gaussian programme suite were carried out with the aim of strengthening experimental structural elucidation. Results Recombinant strains of Amycolatopsis sulphurea producing atypical tetracyclines chelocardin, modified chelocardin analogues (9‐demethylchelocardin and 2‐carboxyamido‐2‐deacetyl‐chelocardin (CDCHD), and anhydrotetracycline (ATC) were analysed by collision‐induced dissociation (CID) fragmentation with higher collision energies to yield structurally important fragments which were identified. We have demonstrated that ATC is more prone to fragmentation compared to its epimer, which was further supported by comparison of both structures calculated with ab initio calculations. Conclusions We have demonstrated that fragmentation patterns of atypical tetracyclines in CID‐MS spectra enable rapid structural elucidation of target metabolites produced by cultures of genetically engineered bacteria. This method is of significant importance for early stages of drug development considering that isolation of target metabolites produced at low concentration is challenging. Copyright © 2015 John Wiley & Sons, Ltd.
    Type of Medium: Online Resource
    ISSN: 0951-4198 , 1097-0231
    URL: Issue
    URL: Article
    DOI: 10.1002/rcm.v29.17
    DOI: 10.1002/rcm.7252
    Language: English
    Publisher: Wiley
    Publication Date: 2015
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    SSG: 11
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  • 12
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    Construction of a New Class of Tetracycline Lead Structures with Potent Antibacterial Activity through Biosynthetic Engineering
    Wiley ; 2015
    In:  Angewandte Chemie Vol. 127, No. 13 ( 2015-03-23), p. 4009-4012
    Details
    In: Angewandte Chemie, Wiley, Vol. 127, No. 13 ( 2015-03-23), p. 4009-4012
    Abstract: Antimicrobial resistance and the shortage of novel antibiotics have led to an urgent need for new antibacterial drug leads. Several existing natural product scaffolds (including chelocardins) have not been developed because their suboptimal pharmacological properties could not be addressed at the time. It is demonstrated here that reviving such compounds through the application of biosynthetic engineering can deliver novel drug candidates. Through a rational approach, the carboxamido moiety of tetracyclines (an important structural feature for their bioactivity) was introduced into the chelocardins, which are atypical tetracyclines with an unknown mode of action. A broad‐spectrum antibiotic lead was generated with significantly improved activity, including against all Gram‐negative pathogens of the ESKAPE panel. Since the lead structure is also amenable to further chemical modification, it is a platform for further development through medicinal chemistry and genetic engineering.
    Type of Medium: Online Resource
    ISSN: 0044-8249 , 1521-3757
    URL: Issue
    URL: Article
    DOI: 10.1002/ange.v127.13
    DOI: 10.1002/ange.201411028
    RVK:
    VA 2100
    RVK:
    VN 5020
    Language: German
    Publisher: Wiley
    Publication Date: 2015
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    detail.hit.zdb_id: 506259-7
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