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ACS Chem Biol. 2017 Sep 15;12(9):2287-2295. doi: 10.1021/acschembio.7b00388. Epub 2017 Jul 26.

Chemical Genomics, Structure Elucidation, and in Vivo Studies of the Marine-Derived Anticlostridial Ecteinamycin.

Author information

1
Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
2
Yumanity Therapeutics , Cambridge, Massachusetts 02139, United States.
3
Department of Medicine, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
4
National Magnetic Resonance Facility at Madison, Department of Biochemistry, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
5
Department of Food Science, University of Wisconsin-Madison , Madison, Wisconsin 53706, United States.
6
Department of Computer Science and Engineering, University of Minnesota-Twin Cities , Minneapolis, Minnesota 55455, United States.
7
Graduate School of Biological Sciences, Nara Institute of Science and Technology , Ikoma, Nara 630-0101, Japan.

Abstract

A polyether antibiotic, ecteinamycin (1), was isolated from a marine Actinomadura sp., cultivated from the ascidian Ecteinascidia turbinata. 13C enrichment, high resolution NMR spectroscopy, and molecular modeling enabled elucidation of the structure of 1, which was validated on the basis of comparisons with its recently reported crystal structure. Importantly, ecteinamycin demonstrated potent activity against the toxigenic strain of Clostridium difficile NAP1/B1/027 (MIC = 59 ng/μL), as well as other toxigenic and nontoxigenic C. difficile isolates both in vitro and in vivo. Additionally, chemical genomics studies using Escherichia coli barcoded deletion mutants led to the identification of sensitive mutants such as trkA and kdpD involved in potassium cation transport and homeostasis supporting a mechanistic proposal that ecteinamycin acts as an ionophore antibiotic. This is the first antibacterial agent whose mechanism of action has been studied using E. coli chemical genomics. On the basis of these data, we propose ecteinamycin as an ionophore antibiotic that causes C. difficile detoxification and cell death via potassium transport dysregulation.

PMID:
28708379
PMCID:
PMC5697710
DOI:
10.1021/acschembio.7b00388
[Indexed for MEDLINE]
Free PMC Article

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