Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain

ABSTRACT 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...

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Autores principales:	Attilio Fabbretti, Retina Çapuni, Anna Maria Giuliodori, Lucia Cimarelli, Antonino Miano, Valerio Napolioni, Anna La Teana, Roberto Spurio
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	self-resistance antibiotic ribosomal protein S12 translation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/992cef27e8be444d9b270146ff23ec31
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spelling	oai:doaj.org-article:992cef27e8be444d9b270146ff23ec312021-11-15T15:27:32ZCharacterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain10.1128/mSphere.00554-192379-5042https://doaj.org/article/992cef27e8be444d9b270146ff23ec312019-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mSphere.00554-19https://doaj.org/toc/2379-5042ABSTRACT 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.Attilio FabbrettiRetina ÇapuniAnna Maria GiuliodoriLucia CimarelliAntonino MianoValerio NapolioniAnna La TeanaRoberto SpurioAmerican Society for Microbiologyarticleself-resistanceantibioticribosomal protein S12translationMicrobiologyQR1-502ENmSphere, Vol 4, Iss 5 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	self-resistance antibiotic ribosomal protein S12 translation Microbiology QR1-502
spellingShingle	self-resistance antibiotic ribosomal protein S12 translation Microbiology QR1-502 Attilio Fabbretti Retina Çapuni Anna Maria Giuliodori Lucia Cimarelli Antonino Miano Valerio Napolioni Anna La Teana Roberto Spurio Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain
description	ABSTRACT 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.
format	article
author	Attilio Fabbretti Retina Çapuni Anna Maria Giuliodori Lucia Cimarelli Antonino Miano Valerio Napolioni Anna La Teana Roberto Spurio
author_facet	Attilio Fabbretti Retina Çapuni Anna Maria Giuliodori Lucia Cimarelli Antonino Miano Valerio Napolioni Anna La Teana Roberto Spurio
author_sort	Attilio Fabbretti
title	Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain
title_short	Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain
title_full	Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain
title_fullStr	Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain
title_full_unstemmed	Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain
title_sort	characterization of the self-resistance mechanism to dityromycin in the <italic toggle="yes">streptomyces</italic> producer strain
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/992cef27e8be444d9b270146ff23ec31
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Characterization of the Self-Resistance Mechanism to Dityromycin in the <italic toggle="yes">Streptomyces</italic> Producer Strain

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