**4. Metabolism Remodeling and Epigenetic Control**

Fully synthetic chemicals also can be utilized as elicitors. ARC2 (**24**, ARC from "Antibiotic-Remodeling-Compound") and similar diphenyl ethers (ARC3–5, **25**–**27**) (Chart 5) have become the first inducer examples discovered by systematic screening of 30,569 small molecules [64,65]. Taking into account the structural similarity of ARC compounds with triclosan (**28**), a well-known biocide and inhibitor of fatty acid biosynthesis, the mechanism of ARCs' action (Chart 5A) has been proposed. Generally, ARCs act as metabolism remodeling compounds, changing the balance between primary and secondary metabolic pathways. The mode of action was confirmed by the experimental data: ARCs changed fatty acid pool by inhibition of key biosynthetic enzymes like FabI. Remarkably, triclosan also can stimulate polyketide antibiotic synthesis at sub-inhibitory concentrations [59]. Further investigation of the different ARCs' effects on the streptomycetes biochemistry revealed the targets for different molecules (even structurally close) as not being the same; however, all of them influenced fatty acid metabolism [66]. Chlorinated analog Cl-ARC (**29**) was used to enhance the expression of cryptic biosynthetic genes, and the observed difference between growth on control and elicitor-containing media was studied using a metabolomics approach. More than 100 induced secondary metabolites were detected, including rare antibiotics [67]. Several identified structures are represented in Chart 6: oxohygrolidin (**30**), germicidins A–E (**31a**–**e**) 9-methylstreptimidone (**32**), nactins (**33**, **34**, **35**), desferrioxamines B,E (**36**, **37**), and arylomycin A4 (**38**).

**Chart 5.** Synthetic diphenyl ethers (ARCs) as elicitors and their mode of action (**A**).

**Chart 6.** Cl-ARC-induced biosynthesis: examples of identified antibiotics [67].

Despite the significant difference in structural DNA organization between eukaryotes and actinomycetes, inhibitors of histone deacetylase (HDAC) like valproic acid (**39**) and suberanilohydroxamic acid (SAHA, **40**) (Chart 7) showed effect on antibiotic production by several *Streptomyces* strains, especially on nutrient-poor media. The finding was explained by the homology between several *S. coelicolor* enzymes (SCO0452, SCO6464, SCO3330) and human HDAC enzymes [68]. Epigenetic modification could be used for the control of antibiotic biosynthesis; the approach, however, is not well studied for actinobacteria.

**Chart 7.** Histone deacetylase (HDAC) inhibitors.
