Actamycin

Two new ansamycin antibiotics, the naphthomycins B and C, were isolated from two different strains of Streptomyces. The structures were determined by comparison of the spectra (UV, 1H NMR, 13C NMR) with those of the known naphthomycin A, by spin decoupling experiments (300 MHz) and in one case by a two dimensional NMR analysis. Naphthomycin B (II) is 30-chloronaphthomycin C. Strikingly, naphthomycin A (I) differs from B and C not only by the presence of an additional methyl group at C (2), but also in the configuration of some of the double bonds. A fourth ansamycin antibiotic of the naphthomycin subgroup, actamycin, is 30-hydroxynaphthomycin C.

Biosynthesis of the ansamycin antibiotic actamycin (2) was markedly increased by the addition of the precursor 3-amino-5-hydroxybenzoic acid (1) to the producing Streptomyces fermentation. Similar addition of the 4-chloro, 6-chloro, N-methyl and O-methyl analogues 4, 6, 5 and 7 of the amino acid 1 reduced actamycin production and did not yield structurally modified ansamycins. These results with the analogues 4, 5 and 7 indicate that the corresponding chlorine, N-methyl and O-methyl substituents present in the nuclei of various ansamycins are introduced at biosynthetic stages beyond the level of the amino acid 1.

Fermentations of Streptomyces sp. E/784 produce low levels of the novel C-30 alkylthio-substituted ansamycin antibiotics naphthomycins J (9) and I (10), in addition to the more abundant C-30 hydroxylated analogues actamycin (1) and naphthomycin D (2) and C-30 chlorinated analogues naphthomycins H (3) and A (4). The addition of N-acetyl-L-cysteine to the fermentation medium substantially increases the production of the thionaphthomycins J and I at the expense of their chloro analogues H and A. Other thiols and thiol progenitors are similarly utilised, including N-acetyl-L-cysteine methyl ester which affords the known naphthomycin F (8) and its novel 2-demethyl homologue (7). The formation of thioansamycins from chloroansamycins and thiols in vivo is probably non-enzymic since similar conversions can be effected in vitro.