Stringent Factor Regulates Antibiotics Production and Morphological Differentiation of Streptomyces clavuligerus

The involvement of the relA and rsh genes in the morphological and physiological differentiation of Streptomyces clavuligerus was evaluated with the relA and rsh genes mutants. The morphological differentiation of S. clavuligerus was greatly affected by the disruption of the relA gene, but not very much by the disruption of the rsh gene. The altered morphological characteristics were completely restored by the complementation of the corresponding disrupted genes. Thus, it was apparent that the mycelial morphology and clavulanic acid production were severely affected by the disruption of the relA gene. Production of clavulanic acid in the submerged batch culture and glycerol-limited chemostat showed that production was inversely related to the specific growth rate in the wild-type strain. However, the production of clavulanic acid in the ${\Delta}relA$ and ${\Delta}rsh$ null mutants was completely abolished. Therefore, it seems plausible that the stringent response of S. clavuligerus to starvation for amino acids is governed mainly by ReIA, rather than Rsh, and that the (p)ppGpp synthesized immediately after the depletion of amino acids triggers the initiation of pathways for both morphological and physiological differentiation in this species.