Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin.
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Authors
Hennessen, FabienneMiethke, Marcus
Zaburannyi, Nestor
Loose, Maria
Lukežič, Tadeja
Bernecker, Steffen
Hüttel, Stephan
Jansen, Rolf
Schmiedel, Judith
Fritzenwanker, Moritz
Imirzalioglu, Can
Vogel, Jörg

Westermann, Alexander J
Hesterkamp, Thomas
Stadler, Marc
Wagenlehner, Florian
Petković, Hrvoje
Herrmann, Jennifer
Müller, Rolf
Issue Date
2020-09-18
Metadata
Show full item recordAbstract
The reassessment of known but neglected natural compounds is a vital strategy for providing novel lead structures urgently needed to overcome antimicrobial resistance. Scaffolds with resistance-breaking properties represent the most promising candidates for a successful translation into future therapeutics. Our study focuses on chelocardin, a member of the atypical tetracyclines, and its bioengineered derivative amidochelocardin, both showing broad-spectrum antibacterial activity within the ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) panel. Further lead development of chelocardins requires extensive biological and chemical profiling to achieve favorable pharmaceutical properties and efficacy. This study shows that both molecules possess resistance-breaking properties enabling the escape from most common tetracycline resistance mechanisms. Further, we show that these compounds are potent candidates for treatment of urinary tract infections due to their in vitro activity against a large panel of multidrug-resistant uropathogenic clinical isolates. In addition, the mechanism of resistance to natural chelocardin was identified as relying on efflux processes, both in the chelocardin producer Amycolatopsis sulphurea and in the pathogen Klebsiella pneumoniae. Resistance development in Klebsiella led primarily to mutations in ramR, causing increased expression of the acrAB-tolC efflux pump. Most importantly, amidochelocardin overcomes this resistance mechanism, revealing not only the improved activity profile but also superior resistance-breaking properties of this novel antibacterial compound.Citation
Antibiotics (Basel). 2020 Sep 18;9(9):E619. doi: 10.3390/antibiotics9090619.Affiliation
HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.; HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.; HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.Publisher
MDPIJournal
Antibiotics (Basel, Switzerland)PubMed ID
32962088Type
ArticleLanguage
enISSN
2079-6382ae974a485f413a2113503eed53cd6c53
10.3390/antibiotics9090619
Scopus Count
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