Modification by genetic changes of the pleiotropic interference of butyrolactone-type autoregulators with differentiation of Streptomyces griseus.

Two series of aerial-mycelium-negative (Amy-), anthracycline-nonproducing (Ant-) mutants were obtained from ancestral Amy+Ant+ strains of S. griseus: a) derivatives represented by the met- strain 39 which could not differentiate although they were still producing both the butyrolactone-type autoregulator 1 and NADP-glycohydrolase, and b) mutants whose incapability to form spores and anthracycline pigments was apparently caused by the loss of autoregulator production. These latter mutants responded to the addition of 1 or the naturally occurring dihydro derivative 2 with complete or at least partial reconstitution of differentiation-associated functions. All of the b)-type mutant strains exhibited similar biochemical alterations in the presence of 1 or 2 regardless of the presence of additional genetic changes in the primary metabolism. Two mutants, however, displayed an altered pattern of secondary product formation. In submerged cultures the major biochemical changes observed in presence of 1 (or 2) were an increase of the lipid level in the mycelium, an alteration of the lipid composition, and a stimulation of neutral proteinase production. All of the blocked autoregulator-negative mutants were discernible from the ancestral strains and strain 39 by their lack of NADP-glycohydrolase production. This suggested the existance of a common genetic locus or a common pleiotropic regulator gene controling both gene functions. Present ideas concerning the role of butyrolactone-type autoregulator 1 as a pleiotropic effector molecule interacting with development of S. griseus are summarized in a hypothetical scheme.