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Amidochelocardin overcomes resistance mechanisms exerted on tetracyclines and natural chelocardin
- Source :
- Antibiotics, vol. 9, no. 9, 619, 2020., Antibiotics, Volume 9, Issue 9, Antibiotics, Vol 9, Iss 619, p 619 (2020), Antibiotics (Basel, Switzerland), Switzerland
- Publication Year :
- 2020
-
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.
- Subjects :
- 0301 basic medicine
Microbiology (medical)
Klebsiella
Klebsiella pneumoniae
clinical isolates
030106 microbiology
chelocardins
poliketidi
medicine.disease_cause
Biochemistry
Microbiology
Article
AcrAB-TolC efflux pump
03 medical and health sciences
Antibiotic resistance
resistance-breaking properties
medicine
Pharmacology (medical)
protimikrobna aktivnost
ddc:610
General Pharmacology, Toxicology and Pharmaceutics
broad-spectrum antibiotics
amidokelokardin
atypical tetracyclines
udc:604.4:615.33
biology
Pseudomonas aeruginosa
Chemistry
lcsh:RM1-950
uropathogens
tertaciklin
biology.organism_classification
Acinetobacter baumannii
urinary tract infection (UTI)
kelokardin
lcsh:Therapeutics. Pharmacology
030104 developmental biology
Infectious Diseases
Staphylococcus aureus
mechanism of resistance
Efflux
antibiotiki
mehanizem delovanja
Enterococcus faecium
Subjects
Details
- Language :
- English
- ISSN :
- 20796382
- Database :
- OpenAIRE
- Journal :
- Antibiotics, vol. 9, no. 9, 619, 2020., Antibiotics, Volume 9, Issue 9, Antibiotics, Vol 9, Iss 619, p 619 (2020), Antibiotics (Basel, Switzerland), Switzerland
- Accession number :
- edsair.doi.dedup.....19bb458ea7f46a7ce373dd9b9b1cd699