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

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

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.

MeSH terms

  • Actinomycetales / chemistry*
  • Animals
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / isolation & purification
  • Anti-Bacterial Agents / pharmacology*
  • Clostridioides difficile / drug effects*
  • Enterocolitis, Pseudomembranous / drug therapy
  • Enterocolitis, Pseudomembranous / microbiology
  • Ethers / chemistry
  • Ethers / isolation & purification
  • Ethers / pharmacology
  • Humans
  • Ionophores / chemistry*
  • Ionophores / isolation & purification
  • Ionophores / pharmacology*
  • Urochordata / microbiology

Substances

  • Anti-Bacterial Agents
  • Ethers
  • Ionophores