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Molecules 2016, 21(7), 824; doi:10.3390/molecules21070824

Activating and Attenuating the Amicoumacin Antibiotics

1
Department of Chemistry, Yale University, New Haven, CT 06520, USA
2
Chemical Biology Institute, Yale University, West Haven, CT 06516, USA
3
Department of Ecology & Evolutionary Biology, Yale University, New Haven, CT 06520, USA
4
Department of Microbial Pathogenesis, Yale School of Medicine, New Haven, CT 06536, USA
*
Author to whom correspondence should be addressed.
Academic Editor: Tobias A. M. Gulder
Received: 17 March 2016 / Revised: 7 June 2016 / Accepted: 20 June 2016 / Published: 24 June 2016
(This article belongs to the Special Issue Biosynthesis of Natural Products)
View Full-Text   |   Download PDF [4458 KB, uploaded 24 June 2016]   |  

Abstract

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. View Full-Text
Keywords: natural product; insect pathogen; isocoumarin; biosynthesis; genome mining; orphan pathway natural product; insect pathogen; isocoumarin; biosynthesis; genome mining; orphan pathway
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Park, H.B.; Perez, C.E.; Perry, E.K.; Crawford, J.M. Activating and Attenuating the Amicoumacin Antibiotics. Molecules 2016, 21, 824.

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