The choice of phosphate/nitrogen source and their concentrations have been shown to have great influences on antibiotic production. However, the underlying mechanisms responsible for this remain poorly understood. We show that nutrient-sensing regulator PhoP (phosphate regulator) binds to and upregulates most of genes (ery cluster genes) involved in erythromycin biosynthesis in Saccharopolyspora erythraea, resulting in increase of erythromycin yield. Furthermore, it was found that PhoP also directly interacted with the promoter region of bldD gene encoding an activator of erythromycin biosynthesis, and induced its transcription. Phosphate limitation and overexpression of phoP increased the transcript levels of ery genes to enhance the erythromycin production. The results are further supported by observation that an over-producing strain of S. erythraea expressed more PhoP than a wild-type strain. On the other hand, nitrogen signal exerts the regulatory effect on the erythromycin biosynthesis through GlnR negatively regulating the transcription of phoP gene. These findings provide evidence that PhoP mediates the interplay between phosphate/nitrogen metabolism and secondary metabolism by integrating phosphate/nitrogen signals to modulate the erythromycin biosynthesis. Our study reveals a molecular mechanism underlying antibiotic production, and suggests new possibilities for designing metabolic engineering and fermentation optimization strategies for increasing antibiotics yield.

中文翻译：

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磷酸调节剂PhoP直接和间接控制红糖酵母中红霉素生物合成基因的转录

磷酸盐/氮源的选择及其浓度已显示对抗生素生产有很大影响。但是，造成这种情况的基本机制仍然知之甚少。我们表明，营养敏感调节剂PhoP（磷酸盐调节剂）结合并上调了参与糖多孢红斑菌中红霉素生物合成的大多数基因（簇簇基因），从而增加了红霉素的产量。此外，发现PhoP还与编码红霉素生物合成激活剂的bldD基因的启动子区域直接相互作用，并诱导其转录。磷酸盐限制和phoP的过表达增加了ery基因的转录水平，从而增强了红霉素的产生。通过观察到过量产生的S菌株，进一步支持了该结果。与野生型菌株相比，红斑表达更多的PhoP。另一方面，氮信号通过负调节phoP基因转录的GlnR对红霉素的生物合成产生调节作用。这些发现提供了证据，PhoP通过整合磷酸盐/氮信号来调节红霉素的生物合成来介导磷酸盐/氮代谢与次级代谢之间的相互作用。我们的研究揭示了抗生素生产的分子机制，并为设计代谢工程和发酵优化策略以增加抗生素产量提供了新的可能性。氮信号通过GlnR负调控phoP基因的转录而对红霉素的生物合成产生调控作用。这些发现提供了证据，PhoP通过整合磷酸盐/氮信号来调节红霉素的生物合成来介导磷酸盐/氮代谢与次级代谢之间的相互作用。我们的研究揭示了抗生素生产的分子机制，并为设计代谢工程和发酵优化策略以增加抗生素产量提供了新的可能性。氮信号通过负调节phoP基因转录的GlnR对红霉素的生物合成产生调节作用。这些发现提供了证据，PhoP通过整合磷酸盐/氮信号来调节红霉素的生物合成来介导磷酸盐/氮代谢与次级代谢之间的相互作用。我们的研究揭示了抗生素生产的分子机制，并为设计代谢工程和发酵优化策略以增加抗生素产量提供了新的可能性。