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Semisynthesis and biological evaluation of amidochelocardin derivatives as broad-spectrum antibiotics.
Grandclaudon, Charlotte Birudukota, N V Suryanarayana Elgaher, Walid A M Jumde, Ravindra P Yahiaoui, Samir Arisetti, Nanaji Hennessen, Fabienne Hüttel, Stephan Herrmann, Jennifer
Grandclaudon, Charlotte
Birudukota, N V Suryanarayana
Elgaher, Walid A M
Jumde, Ravindra P
Yahiaoui, Samir
Arisetti, Nanaji
Hennessen, Fabienne
Hüttel, Stephan
Herrmann, Jennifer
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2019-12-20
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Abstract
To address the global challenge of emerging antimicrobial resistance, the hitherto most successful strategy to new antibiotics has been the optimization of validated natural products; most of these efforts rely on semisynthesis. Herein, we report the semisynthetic modification of amidochelocardin, an atypical tetracycline obtained via genetic engineering of the chelocardin producer strain. We report modifications at C4, C7, C10 and C11 by the application of methylation, acylation, electrophilic substitution, and oxidative C-C coupling reactions. The antibacterial activity of the reaction products was tested against a panel of Gram-positive and Gram-negative pathogens. The emerging structure-activity relationships (SARs) revealed that positions C7 and C10 are favorable anchor points for the semisynthesis of optimized derivatives. The observed SAR was different from that known for tetracyclines, which underlines the pronounced differences between the two compound classes.
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Eur J Med Chem. 2019 Dec 20;188:112005. doi: 10.1016/j.ejmech.2019.112005.
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en
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1768-3254
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Attribution-NonCommercial-ShareAlike 4.0 International