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The soil bacteria responsible for producing various metabolites are widely underappreciated. Streptomycetes in particular have given us a number of useful compounds of various chemical structures, so-called secondary metabolites, including antibiotics. Antibiotic production in Streptomyces spp. is believed to occur in a growth-phasedependent manner. Studies of Streptomyces coelicolor A3(2) have shown that the biosynthetic pathway for two antibiotics, actinorhodin (Act) and undecylprodigilsin (Red), are positively regulated at the transcriptional level by their own pathway-specific regulatory proteins, ActIIORF4 and RedD, and that either of their transcriptional expressions occur at the end of the exponential phase1, 2). Our interest lies in the regulation that occurs during this period, the end of the exponential phase. Stringent response is one of the best-studied events observed during this period. It is a commonly occurring bacterial regulatory response initiated by nutrient limitation, causing immediate cessation of RNA accumulation. The guanine nucleotides ppGpp and pppGpp are believed to be responsible for the stringent response. It has been established that the synthesis of the ppGpp molecule correlates with antibiotic production in some Streptomyces species and with transcriptional expression of regulatory proteins in S. coelicolor A3(2)1–3). On the other hand, we have found that defined mutations in rpsL genes (encoding the ribosomal S12 protein) activate antibiotic production in various bacteria4–6). These mutations, involving the alteration of the Lys-88 amino acid in ribosomal protein S12 to Glu, elicit Act and Red production in S. lividans 66, and enhance the productivity of these antibiotics in S. coelicolor A3(2) more than 5-fold. In addition, these mutations successfully restored impaired antibiotic production resulting from relA or relC mutations in which ppGpp productivity is absent6, 7). Compared to the regulatory mechanism involving the ppGpp system that regulates antibiotic production at the transcriptional level, this S12 system appears to play a role at the translational level. We have begun to clarify the mechanism underlying this phenomenon. Characterization of str mutants. The substitution of Lys-88 with Glu in the S12 protein conferred high resistance to streptomycin, in addition to activating antibiotic production. On the other hand, the substitution of Lys-43 with Asp did not affect antibiotic production, although this mutation also conferred high resistance to streptomycin. The transcription and translation levels of pathway-specific regulators (ActII-ORF4 and RedD) were both significantly increased in the K88E mutant, as demonstrated by RNase protection assays (Okamoto and Ochi, unpublished results) and by Western blot analyses. A single amino acid substitution in ribosomal protein S12 resulted in the following streptomycinresistant mutants: K43N, K43T, K43R, K88R, K88E, and P91S. Four mutants (K43N, K43T, K43R, and K88R) exhibited no changes in antibiotic production, while the antibiotic production of two (K88E and P91S) enhanced significantly (more than 5-fold) the production of Act. All these rpsL mutants tested, from S. coelicolor and S. lividans, exhibited a marked increase in translational accuracy (i.e., decrease in missense error rate). These results indicate that the accuracy level of each mutant strain does not correlate with Act overproduction found in certain rpsL mutants8).

Activation of Potential Function in Streptomyces for the Regulation of Secondary Metabolism