Chemical Genomics, Structure Elucidation, and in Vivo Studies of the Marine-Derived Anticlostridial Ecteinamycin
Abstract
A polyether antibiotic, ecteinamycin (1), was isolated from a marine Actinomadura sp., cultivated from the ascidian Ecteinascidia turbinata. C-13 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/mu L), 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Nov 21, 2017
- Accession Number
- AD1122210
Entities
People
- Chad L. Myers
- Doug R Braun
- Gabriel Cornilescu
- Gregory A. Ellis
- Hirotada Mori
- James Steele
- Jeff S Piotrowski
- John L Markley
- Justin Nelson
- Megan N Duster
- Nasia Safdar
- Rene F Ramos Alvarenga
- Scott R Rajski
- Scott W Simpkins
- Simone R Warrack
- Thomas P Wyche
- Tim S Bugni
- Travis J De Wolfe
- Yanpeng Hou
Organizations
- United States Naval Research Laboratory