Characterization of the Self-Resistance Mechanism to Dityromycin in the Streptomyces Producer Strain.

Autor:	Fabbretti A; Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy., Çapuni R; Structural Biology Unit, CIC bioGUNE, Derio, Bizkaia, Spain., Giuliodori AM; Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy., Cimarelli L; Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy., Miano A; Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy., Napolioni V; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA., La Teana A; Department of Life and Environmental Sciences, Polytechnic University of Marche, Ancona, Italy., Spurio R; Laboratory of Genetics, School of Biosciences and Veterinary Medicine, University of Camerino, Camerino, Italy roberto.spurio@unicam.it.
Jazyk:	angličtina
Zdroj:	MSphere [mSphere] 2019 Sep 25; Vol. 4 (5). Date of Electronic Publication: 2019 Sep 25.
DOI:	10.1128/mSphere.00554-19
Abstrakt:	Dityromycin is a peptide antibiotic isolated from the culture broth of the soil microorganism Streptomyces sp. strain AM-2504. Recent structural studies have shown that dityromycin targets the ribosomal protein S12 in the 30S ribosomal subunit, inhibiting translocation. Herein, by using in vitro protein synthesis assays, we identified the resistance mechanism of the producer strain to the secondary metabolite dityromycin. The results show that the self-resistance mechanism of the Streptomyces sp. strain AM-2504 is due to a specific modification of the ribosome. In particular, two amino acid substitutions, located in a highly conserved region of the S12 protein corresponding to the binding site of the antibiotic, were found. These mutations cause a substantial loss of affinity of the dityromycin for the 30S ribosomal subunit, protecting the producer strain from the toxic effect of the antibiotic. In addition to providing a detailed description of the first mechanism of self-resistance based on a mutated ribosomal protein, this work demonstrates that the molecular determinants of the dityromycin resistance identified in Streptomyces can be transferred to Escherichia coli ribosomes, where they can trigger the same antibiotic resistance mechanism found in the producer strain. IMPORTANCE The World Health Organization has identified antimicrobial resistance as a substantial threat to human health. Because of the emergence of pathogenic bacteria resistant to multiple antibiotics worldwide, there is a need to identify the mode of action of antibiotics and to unravel the basic mechanisms responsible for drug resistance. Antibiotic producers' microorganisms can protect themselves from the toxic effect of the drug using different strategies; one of the most common involves the modification of the antibiotic's target site. In this work, we report a detailed analysis of the molecular mechanism, based on protein modification, devised by the soil microorganism Streptomyces sp. strain AM-2504 to protect itself from the activity of the peptide antibiotic dityromycin. Furthermore, we demonstrate that this mechanism can be reproduced in E. coli , thereby eliciting antibiotic resistance in this human commensal bacterium. (Copyright © 2019 Fabbretti et al.)
Databáze:	MEDLINE
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