This is the reason why benzyl thiocyanate is able to raise the antibiotic production only if it is added in the lag phase, growth phase or at the beginning of the production phase. Its effect is more pronounced in low production strains, where the enzymes of secondary metabolism level and the antibiotic production are increased 10 to 20-fold, as compared to high production strains where the increase is only twofold. the streptomycete antibiotic producers, low-molecular, diffusible compounds have been discovered that regulate the metabolism of the producer, where they are present at very low concentrations, and thus affect both the biochemical and morphological differentiation. The most famous of them is factor A, gamma-butyrolactone, that was discovered in Streptomyces griseus producing streptomycin. A non-producing strain started the synthesis of streptomycin after factor A was added to the culture and, in parallel, the formation of aerial mycelium was taking place. Factor A is synthesized by many streptomycetes but the regulatory effect was observed only in Streptomyces griseus, Streptomyces bikiniensis and Streptomyces actuosus. As the result of the addition of factor A to blocked mutants of Streptomyces griseus JA 5142, the synthesis of anthracyclines and leukaemomycin (anthracycline type antibiotic) was resumed. The resistance to streptomycin linked with an enzymatic phosphorylation of the antibiotic is also induced by factor A.
Analogues of factor A have also been found, all of them being gamma-butyrolactones. Virginiae butanolides were detected in Streptomyces virginiae. Factor I was isolated from Streptomyces sp. FR1-5 and its effective concentration was 0.6 ng/ml culture. Most of the factor A analogues, however, were not biologically active.B was isolated from the yeast Saccharomyces cerevisiae. This substance was capable of eliciting the production of rifamycin in a blocked mutant of Nocardia sp. This substance was effective at a concentration of 10 - 8 M, when one molecule elicited a synthesis of about 1500 molecules of the antibiotic. The structure of factor B is similar to cAMP but none of the derivatives of known nucleotides exhibited a comparable effect. Chemically prepared derivatives of factor B have also been tested. The effect was observed with those that had a C 2 -C 12 acyl moiety; octylester was the most effective of them, exhibiting the effect at as low a concentration as 10 - 10 M. A substitution of guanosine for adenine did not result in a loss of the biological activity of factor B. C was isolated from the fermentation medium of Streptomyces griseus. This compound causes cytodifferentiation of non-differentiating mutants. Factor C is a protein having a molecular weight of about 34500 D, whose molecule is rich in hydrophobic amino acids. The effect of autoregulators is easily observable, if they elicit morphological changes, such as the formation of aerial mycelium. Carbazomycinal and 6-methoxcarbazomycinal, isolated from Streptoverticillium species, were capable of inhibition of the aerial mycelium formation at a concentration of 0.5 to 1 microgram per ml. Autoregulators affecting sporulation were found in Streptomyces venezuelae, Streptomyces avermitilis), and Streptomyces viridochromogenes NRRL B - 1551. From the same strain of Streptomyces viridochromogenes, germicidin was isolated by Petersen and co-workers [21]. The compound had an inhibitory effect on the germination of arthrospores of Streptomyces viridochromogenes at a concentration as low as 40 picograms per ml. Germicidin (6- (2-butyl) - 3-ethyl - 4-hydroxy - 2-pyrone) is the first known autoregulative inhibitor of spore germination in the genus Streptomyces and was isolated from the supernatant of germinated spores, but also from the supernatant of a submerged culture.Mutants of Streptomyces cinnamonensis resistant to high concentrations of butyrate and isobutyrate produce an anti-isobutyrate factor, that is excreted into the culture medium. On plates, anti-isobutyrate factor efficiently counteracted toxic concentrations of isobutyrate, acetate, propionate, butyrate, 2-methylbutyrate, valerate, and isovalerate in Streptomyces cinnamonensis and other Streptomyces species.General control mechanisms have been looked for that operate in the antibiotic biosynthesis. The energetic state of the cell is thought to be such a general control mechanism. The intracellular ATP level reflects the content of free energy in the cell. In some cases, the start of the antibiotic synthesis is linked with a decrease of the intracellular ATP level. Such a relationship was observed in Streptomyces aureofaciens and Streptomyces fradiae during the production of tetracycline and tylosin, respectively.
Even though the regulatory role of ATP can not be strictly excluded, the results seem to support a hypothesis that a higher ATP level is accompanying the active pr...
