5-Hydroxy ericamycin, a new anthraquinone with potent antimicrobial activity

Abstract

The departure of many pharmaceutical companies from antibiotic research starting in the 1980s resulted in the absence of new antibiotics to combat the current crisis of increasing microbial resistance to currently available antibiotics. In an effort to address the increasing need for novel antibiotics, AMRI began a screening campaign to identify potent compounds from our natural product library. Natural products, particularly those produced by microbial fermentation, were the direct source or inspiration for almost all antibiotics used today and remain the richest source for new antibacterial compound series. AMRI's extensive library consisting of over 280 000 samples was screened for activity against a multi-drug resistant strain of Staphylococcus aureus (ATCC 43 300, Rockville, MD, USA). The hits arising out of this assay were then tested against the human hepatocellular carcinoma cell line HepG2 to filter out those samples where activity was the result of general cytotoxicity and determine an in vitro therapeutic index (in vitro TI). Samples with a high in vitro TI were selected for fractionation and dereplication. The resulting subset of samples possessing selectivity for the bacterial target were then fractionated on an HPLC system employing UV, ELSD (evaporative light scattering) and MS detectors. The eluted fractions were collected into 96-well microtiter plates and submitted for bioassay. LC/MS data for the active fractions generated UV spectra and molecular weights, which were used to search internal and external databases. 1 The analysis of the extract from strain 4731, which exhibited excellent activity against several Gram-positive organisms, resulted in the discovery of a new anthraquinone, which was closely related to the known antibiotic ericamycin. 2,3 Here we report the isolation, structure elucidation and biological activities of 1.The Actinoplanes sp. strain 4731 was isolated from a soil sample collected from grassland near Nanton, in Alberta, Canada. The culture was isolated by a previously described capillary chemotaxis technique, 4 using 0.18% mannitol as a chemo-attractant, spread-plating on water-yeast extract agar plates 5 and incubating in the dark at 28 1C for 10 days. All colonies visible under a dissecting scope were transferred to and purified on starch casein agar plates. Pure cultures were macerated and stored in a 10% glycerol/5% lactose solution at À80 1C. Before fermentation, the culture was streaked from a cryovial onto starch casein agar to verify purity. Fresh culture macerate was prepared from these agar plates after 14 days and used to inoculate the fermentation. Strain 4731 was identified by sequencing of the 16S rRNA gene. Genomic DNA was isolated from a culture grown in tryptic soy broth for 7 days at 28 1C by a phenol:chloroform extraction method. 6 The 16S rRNA gene was amplified using Taq polymerase (Promega, Madison, WI, USA) and the following two primer pairs: 27F, 5 0 -AGA GTTTGATCMTGGCTCAG-3 0 ; 1115R, 5 0 -AGGGTTGCGCTCGTTG-3 0 ; and 339F, 5 0 -CTCCTACGGGAGGCAGCA...

Exploring Anthraquinones as Antibacterial and Antifungal agents

“… [85] A novel anthraquinone namely 5‐hydroxy ericamycin 72 was isolated from Actinoplanes sp. 4731 and the compound showed excellent antibacterial activity against a wide range of pathogens including E. faecium , S. aureus , K. pneumoniae , and P. aeruginosa [86] …”

“…4731 and the compound showed excellent antibacterial activity against a wide range of pathogens including E. faecium, S. aureus, K. pneumoniae, and P. aeruginosa. [86] Another novel anthraquinone, dimer of 1,5,7-trihydroxy-3hydroxylmethylanthraquinone 73, displayed significant antibacterial and antifungal activity (Figure 4). [87] In a recent study, the effect of co-culture on the production of natural products was tested with Streptomyces sp.…”

A review on hydroxy anthraquinones from bacteria: crosstalk’s of structures and biological activities

“…Rarely, HAQ with a complex structure like anthraquinone-γ-pyrones, ericamycin, and enediynes were also reported (Murphy et al, 2010;Rhea et al, 2012;Liang et al, 2010). The aloesaponarin-II (1,8-dihydroxy anthraquinone) is the first HAQ isolated from mutant strains of Streptomyces coelicolor B22 and B159, (Rudd et al, 1979) Streptomyces sp.…”

“…A new anthraquinone, 5-hydroxy ericamycin with potent antimicrobial activity, was extracted from the fermentation broth of the Actinoplanes sp. strain 4731 (Rhea et al, 2012). Some of the enediynes are considered as a class of fused anthraquinones of a 10 member group with sub-nanomolar inhibitory concentrations against a broad group of cancer cell lines.…”

Effectual components of Polygonum ciliinerve protects against Staphylococcus aureus infection with immunomodulatory functions in C57BL/6 mice

“…The most effective chemical ingredients of rPC are polysaccharide and anthraquinones, including emodin, chrysophanol, physcion, rhein, and so forth 5,6 . With the immunomodulatory effect of polysaccharide and the antimicrobial activity of anthraquinones, rPC has been found to possess antimicrobial, antiviral, antioxidant and antitumor activities [6][7][8][9] . However, these studies mainly focused on the in vitro effect of rPC.…”