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. 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.

Marine natural products

“…Drug sensitive strains of E. coli were shown to be potassium cation transport and homeostasis barcode deletion mutants, and this supported an ionophoric mechanism for ecteinamycin induced bacteria cell death. 30 Ecteinamycin 27 has now been isolated from both marine-and soilderived Actinomadura strains, with the latter studies (also reported in 2017) 31 securing the absolute conguration via X-ray diffraction studies.…”

Biological and Chemical Diversity of Ascidian-Associated Microorganisms

“…from Ecteinascidia turbinata led to the purification of ecteinamycin ( 22 ). It showed potent antimicrobial activity against Clostridium difficile NAP1/B1/027 [ 47 ].…”

Description of the bacterial RNA polymerase inhibitor GE23077-producer Actinomadura sp. NRRL B-65521T as Actinomadura lepetitiana sp. nov.

“…They have also been isolated from bovine manure compost [20] and from sewage ditch [21]. Additionally, strains of this genus have been reported as the agents of actinomycete mycetoma [22], whereas others have shown the potential to produce antibiotics [10, 19, 23–27].…”