Directed biosynthesis of new indolmycins

Abstract

Tryptophan in a concentration of 0.4 μg/ml increased the production of indolmycin by 37%. The lipophilic character of indolmycin was reduced via directed biosynthesis by substituting the aromatic ring system with a methoxy or hydroxy group in the 5-position of the antibiotic. This substitution was achieved by the addition of the corresponding tryptophan and indole precursors to a growing culture of Streptomyces griseus ATCC 12648. The more hydrophilic indolmycin derivatives displayed a moderate increase in antimicrobial activity as compared to indolmycin, but did not markedly change the Gram-positive/Gram-negative ratio of activity. Thin-layer chromatography and mass spectrometry showed that additives substituted in the 6-position were not incorporated into the molecule. Antibiotic titer was reduced by addition of the modified precursors, especially in the case of the precursors substituted in the 6-position. Indolmycin, a tryptophan analog, inhibits tryptophanyl t-RNA ligase in cell-free systems from Gram-positive and Gram-negative bacteria1). Despite this, the spectrum of antibacterial activity is restricted mainly to Gram-positive bacteria2,3,4). In Staphylococcus aureus and Bacillus subtilis, indolmycin is transported by the uptake systems for tryptophan5). Because a comparable transport system is present in Escherichia coli, the poor activity of indolmycin against Gram-negative bacteria might be explained by the failure of this hydrophobic antibiotic to penetrate through the hydrophilic barrier of the Gram-negative outer membrane. The biosynthesis of indolmycin originates from tryptophan, arginine and methionine6,7). In an attempt to reduce the lipophilic character of the antibiotic, substitution of the aromatic ring system with a methoxy or a hydroxy group was investigated by means of directed biosynthesis. © 1981, JAPAN ANTIBIOTICS RESEARCH ASSOCIATION. All rights reserved.