20.500.12556/RUL-134488 Amidochelocardin overcomes resistance mechanisms exerted on tetracyclines and natural chelocardin 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. chelocardins atypical tetracyclines broad-spectrum antibiotics clinical isolates uropathogens urinary tract infection (UTI) resistance-breaking properties mechanism of resistance AcrAB-TolC efflux pump antibiotiki poliketidi tertaciklin kelokardin amidokelokardin mehanizem delovanja protimikrobna aktivnost true false true Angleški jezik Slovenski jezik Članek v reviji 2022-01-18 11:50:01 2022-01-18 11:50:02 2022-09-13 03:55:28 0000-00-00 00:00:00 2020 0 0 18 str. iss. 9, art. 619 Vol. 9 2020 0000-00-00 Zaloznikova Objavljeno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 604.4:615.33 2079-6382 10.3390/antibiotics9090619 33973251 RAZ_Hennessen_Fabienne_2020.pdf RAZ_Hennessen_Fabienne_2020.pdf 1 0FC468176EDBFAFF0BF1FBC731C141D6 37dd035476b34111e4886333dcacfac271965f0728fa2e0a79ae0893a33d4d72 924802fd-784c-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=152983 https://www.mdpi.com/2079-6382/9/9/619 1 32d4d019-784c-11ec-abdb-00155dcfd717 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=152981 Biotehniška fakulteta 0 0 0