# The Link between Purine Metabolism and Production of Antibiotics in _Streptomyces_
## 5 Guanosine Metabolism Impinges on Antibiotic Production
### Production of Other Antibiotics  
(p)ppGpp has also been implicated in controlling the antibiotic production in other _Streptomyces_ spp. For example, an _S. antibioticus relA_ mutant is deficient in (p)ppGpp synthesis and actinomycin production, a deficiency that is not alleviated by growth under phosphate-limiting conditions [69]. In _S. griseus_, inhibition of GMP synthetase/GuaA (and hence GTP and (p)ppGpp production) by addition of decoyinine leads to formation of aerial mycelium, but a decrease in the production of streptomycin [23]. A _rel_ mutant (tentatively identified as a _relC_ mutant) fails to accumulate (p)ppGpp in response to nutrient limitation, and it is deficient in both formation of aerial mycelium and submerged spores and in production of enzymes required for streptomycin biosynthesis. In this _rel_ mutant, the addition of decoyinine is accompanied by a marked reduction in cellular GTP levels and it restores the generation of submerged spores; this indicates that morphological differentiation is initiated when GTP levels decrease, but that streptomycin biosynthesis requires (p)ppGpp.  
In _S. clavuiligerus_, inactivation of _relA_ leads to the expected failure to accumulate (p)ppGpp and an inability to sporulate. However, production of clavuanic acid and cephamycin C and transcription of biosynthetic genes is increased in the _rel_ mutant, indicating that antibiotic production is negatively regulated by (p)ppGpp [27]. Curiously, the production of these antibiotics in a _relA_ mutant strain also appears to depend on strain background and/or growth media as reflected in a separate study in which an _S. clavuiligerus relA_ disruptant strain was deficient in antibiotic production [71]. The general role of  
\begin{table}
\begin{tabular}{c c c} \hline \hline
**Species** & **Factor** & **Link to Guanosine Metabolism or Antibiotic Production** \\ \hline _S. coelicolor_ & RelA & (p)ppGpp synthesis, ACT/RED production [64] \\ _S. coelicolor_ & RelC (RplK) & (p)ppGpp synthesis, ACT/RED production [68] \\ _S. coelicolor_ & EshA & (p)ppGpp synthesis, ACT production [67] \\ _S. coelicolor_ & XdhR & Xdh and (p)ppGpp synthesis, ACT production [51; 56; 58] \\ _S. coelicolor_ & RmdA, RmdB & c-di-GMP degradation, ACT production [30] \\ _S. coelicolor_ & CdgA, CdgB & c-di-GMP synthesis, ACT production [31] \\ _S. antibiotics_ & RelA & (p)ppGpp synthesis, actinomycin production [69] \\ _S. antibioticus_ & RelC & (p)ppGpp synthesis, actinomycin production [70] \\ _S. clavuiligerus_ & RelA & (p)ppGpp synthesis, clavuanic acid and cephamycin C production [27; 71] \\ _S. griseus_ & Rel & (p)ppGpp synthesis, streptomycin production [23] \\  & GuaA & \\ \hline \hline \end{tabular}
\end{table}
Table 1: Examples of factors involved in antibiotic production in _Streptomyces_ spp. that are linked to stress response or GTP synthesis.  
(p)ppGpp in eliciting an upregulation of antibiotic production in a number of bacterial species has also motivated efforts towards metabolic engineering by expressing a (p)ppGpp synthetase. In the actinomycete _Saccharomyces erythraea_, this approach yields increased production of erythromycinycin, but only in a wild-type strain and not in an industrial strain, which already exhibits elevated (p)ppGpp levels [72].