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Activating and Attenuating the Amicoumacin Antibiotics

The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been is...

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Autores principales: Park, Hyun Bong, Perez, Corey E., Perry, Elena Kim, Crawford, Jason M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055758/
https://www.ncbi.nlm.nih.gov/pubmed/27347911
http://dx.doi.org/10.3390/molecules21070824
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author Park, Hyun Bong
Perez, Corey E.
Perry, Elena Kim
Crawford, Jason M.
author_facet Park, Hyun Bong
Perez, Corey E.
Perry, Elena Kim
Crawford, Jason M.
author_sort Park, Hyun Bong
collection PubMed
description The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been isolated from Gram-positive Bacillus and Nocardia species. Here, we report the stimulation of a “cryptic” amicoumacin pathway in the entomopathogenic Gram-negative bacterium Xenorhabdus bovienii, a strain not previously known to produce amicoumacins. X. bovienii participates in a multi-lateral symbiosis where it is pathogenic to insects and mutualistic to its Steinernema nematode host. Waxmoth larvae are common prey of the X. bovienii-Steinernema pair. Employing a medium designed to mimic the amino acid content of the waxmoth circulatory fluid led to the detection and characterization of amicoumacins in X. bovienii. The chemical structures of the amicoumacins were supported by 2D-NMR, HR-ESI-QTOF-MS, tandem MS, and polarimeter spectral data. A comparative gene cluster analysis of the identified X. bovienii amicoumacin pathway to that of the Bacillus subtilis amicoumacin pathway and the structurally-related Xenorhabdus nematophila xenocoumacin pathway is presented. The X. bovienii pathway encodes an acetyltransferase not found in the other reported pathways, which leads to a series of N-acetyl-amicoumacins that lack antibacterial activity. N-acetylation of amicoumacin was validated through in vitro protein biochemical studies, and the impact of N-acylation on amicoumacin’s mode of action was examined through ribosomal structural analyses.
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spelling pubmed-50557582016-10-08 Activating and Attenuating the Amicoumacin Antibiotics Park, Hyun Bong Perez, Corey E. Perry, Elena Kim Crawford, Jason M. Molecules Article The amicoumacins belong to a class of dihydroisocoumarin natural products and display antibacterial, antifungal, anticancer, and anti-inflammatory activities. Amicoumacins are the pro-drug activation products of a bacterial nonribosomal peptide-polyketide hybrid biosynthetic pathway and have been isolated from Gram-positive Bacillus and Nocardia species. Here, we report the stimulation of a “cryptic” amicoumacin pathway in the entomopathogenic Gram-negative bacterium Xenorhabdus bovienii, a strain not previously known to produce amicoumacins. X. bovienii participates in a multi-lateral symbiosis where it is pathogenic to insects and mutualistic to its Steinernema nematode host. Waxmoth larvae are common prey of the X. bovienii-Steinernema pair. Employing a medium designed to mimic the amino acid content of the waxmoth circulatory fluid led to the detection and characterization of amicoumacins in X. bovienii. The chemical structures of the amicoumacins were supported by 2D-NMR, HR-ESI-QTOF-MS, tandem MS, and polarimeter spectral data. A comparative gene cluster analysis of the identified X. bovienii amicoumacin pathway to that of the Bacillus subtilis amicoumacin pathway and the structurally-related Xenorhabdus nematophila xenocoumacin pathway is presented. The X. bovienii pathway encodes an acetyltransferase not found in the other reported pathways, which leads to a series of N-acetyl-amicoumacins that lack antibacterial activity. N-acetylation of amicoumacin was validated through in vitro protein biochemical studies, and the impact of N-acylation on amicoumacin’s mode of action was examined through ribosomal structural analyses. MDPI 2016-06-24 /pmc/articles/PMC5055758/ /pubmed/27347911 http://dx.doi.org/10.3390/molecules21070824 Text en © 2016 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Park, Hyun Bong
Perez, Corey E.
Perry, Elena Kim
Crawford, Jason M.
Activating and Attenuating the Amicoumacin Antibiotics
title Activating and Attenuating the Amicoumacin Antibiotics
title_full Activating and Attenuating the Amicoumacin Antibiotics
title_fullStr Activating and Attenuating the Amicoumacin Antibiotics
title_full_unstemmed Activating and Attenuating the Amicoumacin Antibiotics
title_short Activating and Attenuating the Amicoumacin Antibiotics
title_sort activating and attenuating the amicoumacin antibiotics
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055758/
https://www.ncbi.nlm.nih.gov/pubmed/27347911
http://dx.doi.org/10.3390/molecules21070824
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