A major taxon of obligate marine bacteria within the order Actinomycetales has been discovered from ocean sediments. Populations of these bacteria (designated MAR 1) are persistent and widespread, spanning at least three distinct ocean systems. In this study, 212 actinomycete isolates possessing MAR 1 morphologies were examined and all but two displayed an obligate requirement of seawater for growth. Forty-five of these isolates, representing all observed seawater-requiring morphotypes, were partially sequenced and found to share characteristic small-subunit rRNA signature nucleotides between positions 207 and 468 (Escherichia coli numbering). Phylogenetic characterization of seven representative isolates based on almost complete sequences of genes encoding 16S rRNA (16S ribosomal DNA) yielded a monophyletic clade within the family Micromonosporaceae and suggests novelty at the genus level. This is the first evidence for the existence of widespread populations of obligate marine actinomycetes. Organic extracts from cultured members of this new group exhibit remarkable biological activity, suggesting that they represent a prolific resource for biotechnological applications.The recently proposed class Actinobacteria (20) is comprised of high-GϩC-content gram-positive bacteria and includes the actinomycetes (order Actinomycetales), whose members have an unparalleled ability to produce diverse secondary metabolites. These bacteria are primarily saprophytic and are best known from soils where they contribute significantly to the turnover of complex biopolymers, such as lignocellulose, hemicellulose, pectin, keratin, and chitin (27). Additionally, nitrogen-fixing actinomycetes of the genus Frankia have one of the broadest host ranges known, forming root nodule symbioses in more than 200 species of flowering plants (7).Despite their importance in soil ecology, actinomycetes are best known as a source of antibiotics. This became apparent in 1940, following Selman Waksman's seminal discovery of actinomycin (24), and was fully realized by the 1980s, when actinomycetes accounted for almost 70% of the world's naturally occurring antibiotics (15). In the past two decades, however, there has been a decline in the discovery of new lead compounds from common soil-derived actinomycetes as culture extracts yield unacceptably high numbers of previously described metabolites. For this reason, the cultivation of rare or novel actinomycete taxa has become a major focus in the search for the next generation of pharmaceutical agents (2).It is interesting that the world's oceans, which cover 70% of the earth's surface and include some of the most biodiverse ecosystems on the planet, have not been widely recognized as an important resource for novel actinomycetes. In fact, the distributions of actinomycetes in the sea remain largely undescribed, and even today, conclusive evidence that these bacteria play important ecological roles in the marine environment has remained elusive. Speculation regarding the existence of indigenous populatio...
We recently reported the cultivation and phylogenetic characterization of a new group of obligate marine actinomycete bacteria that is widely distributed in ocean sediments.[1] Analogous soil-derived actinomycetes have been the single most significant source of naturally occurring microbial antibiotics, [2] thus the discovery of a major new group of these bacteria in marine sediments suggests that the ocean represents an overlooked habitat from which to isolate these important microorganisms. Given that the rate of discovery of new biologically active compounds from common soil actinomycetes has been falling, [3] obligate marine actinomycetes represent a new resource for structurally diverse secondary metabolites.To date, we have isolated in excess of 2500 strains belonging to this new taxon for which we have proposed the genus name ™Salinospora∫ (a formal taxonomic description is in progress). ™Salinospora∫ strains, with previously undescribed 16S rRNA gene sequences, have been recovered from five distinct tropical/subtropical ocean systems [1] and from depths as great as À1100 m, which indicates that they represent a widely distributed and taxonomically diverse group of sediment bacteria. All isolates display an obligate requirement of ionic sodium for growth, thus indicating a high level of marine adaptation.In preliminary screening, a high percentage of the organic extracts of cultured ™Salinospora∫ strains possessed antibiotic and anticancer activities, which suggests that these bacteria are an excellent resource for drug discovery. Herein we report the results of our first chemical investigation of a member of the ™Salinospora∫ group and show that strain CNB-392 produces the chemically unique and highly bioactive metabolite salinosporamide A (1, Scheme 1). Salinosporamide A exhibits potent cancer cell cytotoxicity and appears to exert its cytotoxic effects through inhibition of the 20S proteasome.™Salinospora∫ strain CNB-392 was isolated from a heattreated marine sediment sample that was plated on a seawater-based agar nutrient medium. Liquid shake flask cultivation of this strain, followed by solid-phase extraction with Amberlite resin (XAD-16) and elution with acetone, resulted in a crude extract that was highly cytotoxic in vitro toward HCT-116 human colon carcinoma (IC 50 ca. 80 ng mL À1 ). Cytotoxicity-guided fractionation of the crude extract led to the isolation of salinosporamide A (1) as a colorless crystalline solid (yield: 7 mg L À1 ). The complete structural assignment of 1 was accomplished by spectral analysis and by a single-crystal X-ray diffraction study.Analysis of the low-resolution mass spectrum of salinosporamide A showed a characteristic [Mþ2] þ peak indicative of the presence of a chlorine atom. High-resolution massspectral analysis provided the molecular formula Comprehensive analysis of 2D NMR data, including the results of COSY, HMQC, and HMBC experiments, enabled the complete planar structure of salinosporamide A to be assigned, as in 1, to a 2-aza-6-oxabicyclo[3.2.0]heptane-3,7...
Starke und selektive Cytotoxizität gegenüber einer Reihe von Krebszelllinien kennzeichnen Salinosporamid A (1), das aus dem Rohextrakt eines einzigartigen marinen Aktinomyceten der Gattung Salinospora isoliert wurde.
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