Dataset Information

Mechanism of CuO nano-particles on stimulating production of actinorhodin in Streptomyces coelicolor by transcriptional analysis.

ABSTRACT: In this research, antibiotic-producing bacteria, Streptomyces coelicolor (S. coelicolor) M145, was exposed to copper oxide (CuO) particles to investigate the effects of nano-particles (NPs) on antibiotic production. Results showed that a higher yield of antibiotics was obtained with smaller particle sizes of CuO NPs. When exposed to 10?mg/L of 40?nm CuO NPs, the maximum amount of actinorhodin (ACT) obtained was 2.6?mg/L after 144?h, which was 2.0-fold greater than that of control. However, the process was inhibited when the concentration of CuO NPs was increased to higher than 20?mg/L. Transcriptome analysis showed that all the genes involved in the ACT cluster were significantly up-regulated after exposure to 10?mg/L NPs, which could be the direct cause of the increase of ACT production. Additionally, some genes related to the generation of acetyl-coA were up-regulated. In this way, CuO NPs led to an increase of secondary metabolites. The mechanism related to these changes indicated that nano-particle?induced ROS and Cu²⁺ played synergetic roles in promoting ACT biosynthesis. This is a first report suggesting that CuO NPs had a significant effect on antibiotic production, which will be helpful in understanding the mechanism of antibiotic production in nature.

SUBMITTER: Liu X

PROVIDER: S-EPMC6677739 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Mechanism of CuO nano-particles on stimulating production of actinorhodin in Streptomyces coelicolor by transcriptional analysis.

Liu Xiaomei X Tang Jingchun J Wang Lan L Liu Rutao R

Scientific reports 20190802 1

In this research, antibiotic-producing bacteria, Streptomyces coelicolor (S. coelicolor) M145, was exposed to copper oxide (CuO) particles to investigate the effects of nano-particles (NPs) on antibiotic production. Results showed that a higher yield of antibiotics was obtained with smaller particle sizes of CuO NPs. When exposed to 10 mg/L of 40 nm CuO NPs, the maximum amount of actinorhodin (ACT) obtained was 2.6 mg/L after 144 h, which was 2.0-fold greater than that of control. However, the p ...[more]

PMID: 31375702

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Project description:Many microorganisms produce secondary metabolites that have antibiotic activity. To avoid self-inhibition, the producing cells often encode cognate export and/or resistance mechanisms in the biosynthetic gene clusters for these molecules. Actinorhodin is a blue-pigmented antibiotic produced by Streptomyces coelicolor. The actAB operon, carried in the actinorhodin biosynthetic gene cluster, encodes two putative export pumps and is regulated by the transcriptional repressor protein ActR. In this work, we show that normal actinorhodin yields require actAB expression. Consistent with previous in vitro work, we show that both actinorhodin and its 3-ring biosynthetic intermediates [e.g., (S)-DNPA] can relieve repression of actAB by ActR in vivo. Importantly, an ActR mutant that interacts productively with (S)-DNPA but not with actinorhodin responds to the actinorhodin biosynthetic pathway with the induction of actAB and normal yields of actinorhodin. This suggests that the intermediates are sufficient to trigger the export genes in actinorhodin-producing cells. We further show that actinorhodin-producing cells can induce actAB expression in nonproducing cells; however, in this case actinorhodin is the most important signal. Finally, while the "intermediate-only" ActR mutant permits sufficient actAB expression for normal actinorhodin yields, this expression is short-lived. Sustained culture-wide expression requires a subsequent actinorhodin-mediated signaling step, and the defect in this response causes widespread cell death. These results are consistent with a two-step model for actinorhodin export and resistance where intermediates trigger initial expression for export from producing cells and actinorhodin then triggers sustained export gene expression that confers culture-wide resistance. IMPORTANCE Understanding the links between antibiotic resistance and biosynthesis is important for our efforts to manipulate secondary metabolism. For example, many secondary metabolites are produced at low levels; our work suggests that manipulating export might be one way to enhance yields of these molecules. It also suggests that understanding resistance will be relevant to the generation of novel secondary metabolites through the creation of synthetic secondary metabolic gene clusters. Finally, these cognate resistance mechanisms are related to mechanisms that arise in pathogenic bacteria, and understanding them is relevant to our ability to control microbial infections clinically.

Project description:The transcription factor AdpA is a key regulator controlling both secondary metabolism and morphological differentiation in Streptomyces. Due to its critical functions, its expression undergoes multilevel regulations at transcriptional, posttranscriptional, and translational levels, yet no posttranslational regulation has been reported. Sulfane sulfur, such as hydro polysulfide (HSnH, n ≥ 2) and organic polysulfide (RSnH, n ≥ 2), is common inside microorganisms, but its physiological functions are largely unclear. Here, we discovered that sulfane sulfur posttranslationally modifies AdpA in Streptomyces coelicolor via specifically reacting with Cys62 of AdpA to form a persulfide (Cys62-SSH). This modification decreases the affinity of AdpA to its self-promoter PadpA, allowing increased expression of adpA, further promoting the expression of its target genes actII-4 and wblA. ActII-4 activates actinorhodin biosynthesis, and WblA regulates morphological development. Bioinformatics analyses indicated that AdpA-Cys62 is highly conserved in Streptomyces, suggesting the prevalence of such modification in this genus. Thus, our study unveils a new type of regulation on the AdpA activity and sheds a light on how sulfane sulfur stimulates the production of antibiotics in Streptomyces. IMPORTANCE Streptomyces species produce a myriad of natural products with (potential) clinical applications. While the database of biosynthetic gene clusters is quickly expanding, their regulation mechanisms are rarely known. Sulfane sulfur species are commonly present in microorganisms with unclear functions. Here, we discovered that sulfane sulfur increases actinorhodin (ACT) production in S. coelicolor. The underlying mechanism is that sulfane sulfur specifically reacts with AdpA, a global transcription factor controlling both ACT gene cluster and morphological differentiation-related genes, to form sulfhydrated AdpA. This modification changes the dynamics of AdpA-controlled gene networks and leads to high expression of ACT biosynthetic genes. Given the wide prevalence of AdpA and sulfane sulfur in Streptomyces, this mechanism may represent a common regulating pattern of all AdpA-controlled biosynthetic pathways. Thus, this finding provides a new strategy for mining and activating valuable biosynthetic gene clusters.

Dataset Information

Mechanism of CuO nano-particles on stimulating production of actinorhodin in Streptomyces coelicolor by transcriptional analysis.

Publications

Mechanism of CuO nano-particles on stimulating production of actinorhodin in Streptomyces coelicolor by transcriptional analysis.

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