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Open AccessArticle

Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin

1
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS)—Helmholtz Centre for Infection Research (HZI), and Department of Pharmacy, Saarland University Campus E8.1, 66123 Saarbrücken, Germany
2
German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, 38124 Braunschweig, Germany
3
Clinic for Urology, Paediatric Urology & Andrology, Justus-Liebig University Gießen, and German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, 35392 Gießen, Germany
4
National Institute of Biology, Večna pot 111, 1000 Ljubljana, Slovenia
5
Department of Microbial Drugs, Helmholtz Centre for Infection Research (HZI), Inhoffenstrasse 7, 38124 Braunschweig, Germany
6
Institute of Medical Microbiology, Justus-Liebig University Gießen, and German Center for Infection Research (DZIF), Partner Site Giessen-Marburg-Langen, 35390 Gießen, Germany
7
Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz Centre for Infection Research (HZI) and Institute of Molecular Infection Biology (IMIB), University of Würzburg, Josef-Schneider-Str. 2, 97080 Würzburg, Germany
8
Department of Food Science and Technology, Biotechnical Faculty, University of Ljubljana, Jamnikarjeva 101, 1000 Ljubljana, Slovenia
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this study.
Antibiotics 2020, 9(9), 619; https://doi.org/10.3390/antibiotics9090619
Received: 23 August 2020 / Revised: 16 September 2020 / Accepted: 17 September 2020 / Published: 18 September 2020
(This article belongs to the Special Issue Novel Targets and Mechanisms in Antimicrobial Drug Discovery)
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. View Full-Text
Keywords: chelocardins; atypical tetracyclines; broad-spectrum antibiotics; clinical isolates; uropathogens; urinary tract infection (UTI); resistance-breaking properties; mechanism of resistance; AcrAB-TolC efflux pump chelocardins; atypical tetracyclines; broad-spectrum antibiotics; clinical isolates; uropathogens; urinary tract infection (UTI); resistance-breaking properties; mechanism of resistance; AcrAB-TolC efflux pump
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Hennessen, F.; Miethke, M.; Zaburannyi, N.; Loose, M.; Lukežič, T.; Bernecker, S.; Hüttel, S.; Jansen, R.; Schmiedel, J.; Fritzenwanker, M.; Imirzalioglu, C.; Vogel, J.; Westermann, A.J.; Hesterkamp, T.; Stadler, M.; Wagenlehner, F.; Petković, H.; Herrmann, J.; Müller, R. Amidochelocardin Overcomes Resistance Mechanisms Exerted on Tetracyclines and Natural Chelocardin. Antibiotics 2020, 9, 619.

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