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首页> 外文期刊>Applied Microbiology >A Hierarchical Network of Four Regulatory Genes Controlling Production of the Polyene Antibiotic Candicidin in Streptomyces sp. Strain FR-008
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A Hierarchical Network of Four Regulatory Genes Controlling Production of the Polyene Antibiotic Candicidin in Streptomyces sp. Strain FR-008

机译：四种调控基因的分层网络，控制Streptomyces SP中的多烯抗生素念珠菌生产。 菌株fr-008

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The four regulatory genes fscR1 to fscR4 in Streptomyces sp. strain FR-008 form a genetic arrangement that is widely distributed in macrolide-producing bacteria. Our previous work has demonstrated that fscR1 and fscR4 are critical for production of the polyene antibiotic candicidin. In this study, we further characterized the roles of the other two regulatory genes, fscR2 and fscR3 , focusing on the relationship between these four regulatory genes. Disruption of a single or multiple regulatory genes did not affect bacterial growth, but transcription of genes in the candicidin biosynthetic gene cluster decreased, and candicidin production was abolished, indicating a critical role for each of the four regulatory genes, including fscR2 and fscR3 , in candicidin biosynthesis. We found that fscR1 to fscR4 , although differentially expressed throughout the growth phase, displayed similar temporal expression patterns, with an abrupt increase in the early exponential phase, coincident with initial detection of antibiotic production in the same phase. Our data suggest that the four regulatory genes fscR1 to fscR4 have various degrees of control over structural genes in the biosynthetic cluster under the conditions examined. Extensive transcriptional analysis indicated that complex regulation exists between these four regulatory genes, forming a regulatory network, with fscR1 and fscR4 functioning at a lower level. Comprehensive cross-complementation analysis indicates that functional complementation is restricted among the four regulators and unidirectional, with fscR1 complementing the loss of fscR3 or - 4 and fscR4 complementing loss of fscR2 . Our study provides more insights into the roles of, and the regulatory network formed by, these four regulatory genes controlling production of an important pharmaceutical compound.IMPORTANCE The regulation of antibiotic biosynthesis by Streptomyces species is complex, especially for biosynthetic gene clusters with multiple regulatory genes. The biosynthetic gene cluster for the polyene antibiotic candicidin contains four consecutive regulatory genes, which encode regulatory proteins from different families and which form a subcluster within the larger biosynthetic gene cluster in Streptomyces sp. FR-008. Syntenic arrangements of these regulatory genes are widely distributed in polyene gene clusters, such as the amphotericin and nystatin gene clusters, suggesting a conserved regulatory mechanism controlling production of these clinically important medicines. However, the relationships between these multiple regulatory genes are unknown. In this study, we determined that each of these four regulatory genes is critical for candicidin production. Additionally, using transcriptional analyses, bioassays, high-performance liquid chromatography (HPLC) analysis, and genetic cross-complementation, we showed that FscR1 to FscR4 comprise a hierarchical regulatory network that controls candicidin production and is likely representative of how expression of other polyene biosynthetic gene clusters is controlled.
机译：四种调节基因FSCR1至Crestomyces SP中的FSCR4。菌株FR-008形成一种遗传布置，其广泛分布在生产大环内酯的细菌中。我们以前的工作表明，FSCR1和FSCR4对于生产多烯抗生素念珠菌至关重要。在这项研究中，我们进一步表征了另外两个调节基因，FSCR2和FSCR3的作用，重点关注这四种调节基因之间的关系。单一或多种调节基因的破坏不影响细菌生长，但在白蛋白生物合成基因簇中的基因转录减少，并消除了烛霉素生产，表明四种调节基因中的每种致力作用，包括FSCR2和FSCR3，包括FSCR2和FSCR3。念珠菌生物合成。我们发现FSCR1至FSCR4，但是在整个生长阶段差异表达，显示出类似的时间表达模式，早期指数阶段突然增加，与相同相中的抗生素产生的初始检测一致。我们的数据表明，在检查的条件下，FSCr1至FSCr4对FSCr1至FSCr4具有各种对生物合成簇中的结构基因的控制。广泛的转录分析表明，在这四种调节基因之间存在复杂的调节，形成调节网络，使用较低水平的FSCR1和FSCR4。综合交叉互补分析表明，功能互补受到四个调节因子和单向的互补性，FSCR1补充FSCR3或-4和FSCR4的FSCR2损失的损失。我们的研究提供了更多的洞察力，并通过这四种调节基因控制了重要的药物化合物的产生的作用和监管网络。分别通过链霉菌物种进行抗生素生物合成的调节，特别是具有多种调节基因的生物合成基因簇。多烯抗生素念珠菌的生物合成基因簇含有四种连续的调节基因，其编码来自不同家族的调节蛋白，并在链霉菌SP中形成较大的生物合成基因簇中的子簇。 FR-008。这些调节基因的同期布置在多烯基因簇中广泛分布，例如两性霉素和阴茎基因簇，表明控制这些临床重要药物的生产的保守监管机制。然而，这些多种调节基因之间的关系是未知的。在这项研究中，我们确定这四种调节基因中的每一个对于念珠菌生产至关重要。另外，使用转录分析，生物测定，高性能液相色谱（HPLC）分析和遗传交叉互补，我们表明FSCR1至FSCR4包括控制念珠菌生产的分层调节网络，可能代表其他多烯生物合成的表达方式控制基因簇。

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