Abyssomicins, Inhibitors of the para-Aminobenzoic Acid Pathway Produced by the Marine Verrucosispora Strain AB-18-032

Abstract

A screening method was established to detect inhibitors of the biosynthetic pathways of aromatic amino acids and para-aminobenzoic acid, the precursor of folic acid, using an agar A successful search for novel antibacterial metabolites has to meet three criteria, first, a specific target which is essential for the metabolism of a bacterium and not yet provided with an known inhibitor. Second, a set of taxonomically characterized and dereplicated microorganisms as producers of secondary metabolites, and last but not least a lucky but experienced hand for strain isolation and cultivation. We have chosen the shikimate pathway as an essential target of bacterial metabolism, with special consideration of the biosynthesis of aromatic amino acids and para-aminobenzoic (pAba) acid derived from the keymetabolite chorismate. Only a few antimetabolites are known as inhibitors of aromatic amino acids, such as L-2,5-dihydrophenylalanine2), an antagonist of phenlyalanine, and glyphosate that inhibits 3-enolpyruvylshikimate-3-phosphate synthase3,4). To our knowledge, no natural product inhibitor of pAba biosynthesis has been described in the literature. This pathway, which is catalyzed by two enzymes, 4-amino-4-deoxychorismic acid (ADC) synthase and ADC lyase, seems to be of considerable interest for the development of novel antibiotics since it is directly linked to folic acid biosynthesis, which is established in plants, fungi, prokaryotes and parasites of the apicomplexa group (Plasmodium, Toxoplasma) but not in vertebrates.As suitable producers of bioactive metabolites we screened within the order Actinomycetales terrestrial and marine members of the families Streptomycetaceae and Micromonosporaceae and rare actinomycete genera. A total of 930 extracts derived from 201 actinomycetes were subjected to the screening. Among them, only AB-18-032, an extract from a marine isolate from a sediment collected from the Sea of Japan, was found to exhibit activity against

Elucidation of the Kijanimicin Gene Cluster: Insights into the Biosynthesis of Spirotetronate Antibiotics and Nitrosugars

“…To definitively identify the new product, the same reaction was carried out on a preparative scale, and the product purified and characterized by 1 H and 31 P NMR spectroscopies and high resolution ESI-MS. The results clearly showed the product is TDP-4-keto-2,6-dideoxy-D-glucose (16), indicating that KijD10 is a 3-ketoreductase.…”

Proximicin A, B and C, Novel Aminofuran Antibiotic and Anticancer Compounds Isolated from Marine Strains of the Actinomycete Verrucosispora†

“…Sediments were collected by box grab from which samples were taken with a sterilized scoop into sterile plastic containers; samples were stored at 4°C. Strain AB-18-032 was isolated from sediment collected from the Sea of Japan at a depth of 289 meters as described previously [4]. The strains were examined for genotypic and phenotypic properties known to be of value in actinobacterial systematics [7].…”

“…Batch fermentations of Verrucosispora strain AB-18-032 were performed as described by Riedlinger et al [4]. Strain MG-37 was cultivated in a 10-liter stirred tank fermentor (Biostat S, B. Braun Melsungen, Germany) in a complex medium that consisted of soluble starch 10 g, glucose 10 g, glycerol 10 g, cornsteep powder (Marcor) 2.5 g, Bacto peptone 5.0 g, yeast extract (Ohly Kat) 2.0 g, NaCl 1.0 g and CaCO 3 3.0 g in 1.0 liter tap water, adjusted to pH 7.3 prior to sterilization.…”

“…The discovery of novel natural products in marine microorganisms has increased linearly over the past two decades while those found in terrestrial microorganisms have remained almost unchanged over the same period [3]. Recently, we reported on the fermentation, isolation and structure elucidation of abyssomicins BϳD, novel polycyclic polyketide antibiotics from the marine actinomycete "Verrucosispora maris" AB-18-032 which was isolated from sediment collected from the Sea of Japan [1,4,5]. The careful evaluation of HPLC chromatograms from extracts of this strain revealed significant amounts of another compound (1) not assignable to any other known compound in our HPLC-UV-Vis database [6].…”

Retymicin, Galtamycin B, Saquayamycin Z and Ribofuranosyllumichrome, Novel Secondary Metabolites from Micromonospora sp. Tü 6368

“…The following secondary metabolites were isolated from strain Tü 6368 and their structures elucidated, (i) rabelomycin [3], 3-deoxyrabelomycin [4] and dehydrorabelomycin [5], (ii) galtamycinone [6] and galtamycin B (2), (iii) saquayamycin Z (3), (iv) lumichrome and 1-methyllumichrome [7], and 1-(a -ribofuranosyl)-lumichrome (4), and (v) retymicin (1). The structures of the new metabolites are shown in Fig.…”