Amidochelocardin overcomes resistance mechanisms exerted on tetracyclines and natural chelocardin

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

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.

• Jezik: Angleški jezik
• Ključne besede: chelocardins, atypical tetracyclines, broad-spectrum antibiotics, clinical isolates, uropathogens, urinary tract infection (UTI), resistance-breaking properties, mechanism of resistance, AcrAB-TolC efflux pump
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: BF - Biotehniška fakulteta
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2020
• Št. strani: 18 str.
• Številčenje: Vol. 9, iss. 9, art. 619
• PID: 20.500.12556/RUL-134488
• UDK: 604.4:615.33
• ISSN pri članku: 2079-6382
• DOI: 10.3390/antibiotics9090619
• COBISS.SI-ID: 33973251
• Datum objave v RUL: 18.01.2022

Gradivo je del revije

• Naslov: Antibiotics
• Skrajšan naslov: Antibiotics
• Založnik: MDPI
• ISSN: 2079-6382
• COBISS.SI-ID: 522975769

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.
• Začetek licenciranja: 18.09.2020

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: antibiotiki, poliketidi, tertaciklin, kelokardin, amidokelokardin, mehanizem delovanja, protimikrobna aktivnost