Fabienne Hennessen (Author), Marcus Miethke (Author), Nestor Zaburannyi (Author), Maria Loose (Author), Tadeja Lukežič (Author), Steffen Bernecker (Author), Rolf Müller (Author), Alexander J. Westermann (Author), Thomas Hesterkamp (Author), Marc Stadler (Author), Florian Wagenlehner (Author), Hrvoje Petković (Author), Jennifer Herrmann (Author), Stephan Hüttel (Author), Rolf Jansen (Author), Judith Schmiedel (Author), Moritz Fritzenwanker (Author), Can Imirzalioglu (Author), Jörg Vogel (Author)

Abstract

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.

Keywords

antibiotiki;poliketidi;tertaciklin;kelokardin;amidokelokardin;mehanizem delovanja;protimikrobna aktivnost;

Data

Language: English
Year of publishing:
Typology: 1.01 - Original Scientific Article
Organization: UL BF - Biotechnical Faculty
UDC: 604.4:615.33
COBISS: 33973251 Link will open in a new window
ISSN: 2079-6382
Views: 165
Downloads: 49
Average score: 0 (0 votes)
Metadata: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Other data

Secondary language: Slovenian
Secondary keywords: antibiotiki;poliketidi;tertaciklin;kelokardin;amidokelokardin;mehanizem delovanja;protimikrobna aktivnost;
Type (COBISS): Article
Pages: str. 1-18
Volume: ǂVol. ǂ9
Issue: ǂiss. ǂ9
Chronology: 2020
DOI: 10.3390/antibiotics9090619
ID: 14306004