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Antibiotics 2018, 7(3), 53; https://doi.org/10.3390/antibiotics7030053

Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus

1
Institut für Organische Chemie, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany
2
Interfakultäres Institut für Mikrobiologie und Infektionsmedizin, Eberhard Karls Universität Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany
3
GEOMAR, Helmholtz-Zentrum für Ozeanforschung Kiel, Düsternbrooker Weg 20, 24105 Kiel, Germany
4
German Center for Infection Research (DZIF), partner site Tübingen, Auf der Morgenstelle 28, 72076 Tübingen, Germany
5
The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kemitorvet bygning 220, 2800 Kongens Lyngby, Denmark
*
Authors to whom correspondence should be addressed.
Received: 4 May 2018 / Revised: 12 June 2018 / Accepted: 22 June 2018 / Published: 28 June 2018
(This article belongs to the Special Issue Actinomycetes: The Antibiotics Producers)
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Abstract

The structural repertoire of bioactive naphthacene quinones is expanded by engineering Streptomyces albus to express the lysolipin minimal polyketide synthase II (PKS II) genes from Streptomyces tendae Tü 4042 (llpD-F) with the corresponding cyclase genes llpCI-CIII. Fermentation of the recombinant strain revealed the two new polyaromatic tridecaketides lysoquinone-TH1 (7, identified) and TH2 (8, postulated structure) as engineered congeners of the dodecaketide lysolipin (1). The chemical structure of 7, a benzo[a]naphthacene-8,13-dione, was elucidated by NMR and HR-MS and confirmed by feeding experiments with [1,2-13C2]-labeled acetate. Lysoquinone-TH1 (7) is a pentangular polyphenol and one example of such rare extended polyaromatic systems of the benz[a]napthacene quinone type produced by the expression of a minimal PKS II in combination with cyclases in an artificial system. While the natural product lysolipin (1) has antimicrobial activity in nM-range, lysoquinone-TH1 (7) showed only minor potency as inhibitor of Gram-positive microorganisms. The bioactivity profiling of lysoquinone-TH1 (7) revealed inhibitory activity towards phosphodiesterase 4 (PDE4), an important target for the treatment in human health like asthma or chronic obstructive pulmonary disease (COPD). These results underline the availability of pentangular polyphenolic structural skeletons from biosynthetic engineering in the search of new chemical entities in drug discovery. View Full-Text
Keywords: lysolipin; minimal PKS II; cyclases; benz[a]naphthacene quinone; tridecaketide; aromatic polyketide; pentacyclic angular polyphenol; extended polyketide chain lysolipin; minimal PKS II; cyclases; benz[a]naphthacene quinone; tridecaketide; aromatic polyketide; pentacyclic angular polyphenol; extended polyketide chain
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Hofeditz, T.; Unsin, C. .-M.; Wiese, J.; Imhoff, J.F.; Wohlleben, W.; Grond, S.; Weber, T. Lysoquinone-TH1, a New Polyphenolic Tridecaketide Produced by Expressing the Lysolipin Minimal PKS II in Streptomyces albus. Antibiotics 2018, 7, 53.

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