Abstract
Cyclic adenosine monophosphate (cAMP) has been known to play an important role in regulating morphological development and antibiotic production in Streptomyces coelicolor. However, the functional connection between cAMP levels and antibiotic production and the mechanism by which cAMP regulates antibiotic production remain unclear. In this study, metabolomics- and transcriptomics-based multi-omics analysis was applied to S. coelicolor strains that either produce the secondary metabolite actinorhodin (Act) or lack most secondary metabolite biosynthesis pathways including Act. Comparative multi-omics analysis of the two strains revealed that intracellular and extracellular cAMP abundance was strongly correlated with actinorhodin production. Notably, supplementation of cAMP improved cell growth and antibiotic production. Further multi-omics analysis of cAMP-supplemented S. coelicolor cultures showed an increase of guanine and the expression level of purine metabolism genes. Based on this phenomenon, supplementation with 7-methylguanine, a competitive inhibitor of reactions utilizing guanine, with or without additional cAMP supplementation, was performed. This experiment revealed that the reactions inhibited by 7-methylguanine are mediating the positive effect on growth and antibiotic production, which may occur downstream of cAMP supplementation.
Highlights
IntroductionStreptomyces species are soil-dwelling Gram-positive Actinobacteria and well-known important sources of bioactive secondary metabolites such as antibiotics (e.g., streptomycin; Davies et al, 1964), immunosuppressants (e.g., FK-506; Kino et al, 1987a,b), and anthelmintics (e.g., avermectin; Ikeda and Omura, 1997)
Streptomyces species are soil-dwelling Gram-positive Actinobacteria and well-known important sources of bioactive secondary metabolites such as antibiotics, immunosuppressants (e.g., FK-506; Kino et al, 1987a,b), and anthelmintics
Multi-omics analysis of cyclic adenosine monophosphate (cAMP)-supplemented cultures was performed to explore how the effects of cAMP are mediated through changes in the S. coelicolor metabolome and transcriptome. These results provide valuable mechanistic insights into the effects of cAMP and their regulation, which in the future might be exploited for manipulating the cell growth and antibiotic production of S. coelicolor
Summary
Streptomyces species are soil-dwelling Gram-positive Actinobacteria and well-known important sources of bioactive secondary metabolites such as antibiotics (e.g., streptomycin; Davies et al, 1964), immunosuppressants (e.g., FK-506; Kino et al, 1987a,b), and anthelmintics (e.g., avermectin; Ikeda and Omura, 1997). The regulation of secondary metabolite production has been a focus of research in natural product discovery and production (Liu et al, 2018). In most cases, it is not fully understood by which mechanism such approaches led to the increased production of secondary metabolites. With the recent rapid progress of analytical equipment and methods that contribute to the accumulation of more analytical data, new opportunities arise for studying the regulation of secondary metabolism. Transcriptome (Hwang et al, 2019), proteome (Millan-Oropeza et al, 2017), metabolome (Senges et al, 2018), and lipidome analyses (Zhang et al, 2020) or various combinations of these (Wang et al, 2017; Gosse et al, 2019) in Streptomyces have been applied to studies of secondary metabolism regulation
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