Andreo-Vidal Andrés, Yushchuk Oleksandr, Marinelli Flavia, Binda Elisa
Department of Biotechnology and Life Sciences, University of Insubria, via J. H. Dunant 3, 21100 Varese, Italy.
Department of Genetics and Biotechnology, Ivan Franko National University of Lviv, 79005 Lviv, Ukraine.
Antibiotics (Basel). 2023 Mar 24;12(4):641. doi: 10.3390/antibiotics12040641.
Teicoplanin and A40926 (natural precursor of dalbavancin) are clinically relevant glycopeptide antibiotics (GPAs) produced by NRRL B-16726 and ATCC 39727. Their biosynthetic enzymes are coded within large biosynthetic gene clusters (BGCs), named for teicoplanin and for A40926, whose expression is strictly regulated by pathway-specific transcriptional regulators (PSRs), coded by cluster-situated regulatory genes (CSRGs). Herein, we investigated the "cross-talk" between the CSRGs from and , through the analysis of GPA production levels in and strains, with knockouts of CSRGs cross-complemented by the expression of heterologous CSRGs. We demonstrated that Tei15* and Dbv4 StrR-like PSRs, although orthologous, were not completely interchangeable: and were only partially able or unable to cross-complement knocked out in and . knocked out in , implying that the DNA-binding properties of these PSRs are more different than it was believed before. At the same time, the unrelated LuxR-like PSRs Tei16* and Dbv3 were able to cross-complement corresponding knocked out in and knocked out in . Moreover, the heterologous expression of in led to a significant increase in teicoplanin production. Although the molecular background of these events merits further investigations, our results contribute to a deeper understanding of GPA biosynthesis regulation and offer novel biotechnological tools to improve their production.
替考拉宁和A40926（达巴万星的天然前体）是由NRRL B - 16726和ATCC 39727产生的具有临床相关性的糖肽类抗生素（GPA）。它们的生物合成酶由大型生物合成基因簇（BGC）编码，替考拉宁的BGC命名为 ，A40926的BGC命名为 ，其表达受到由簇内调控基因（CSRG）编码的途径特异性转录调节因子（PSR）的严格调控。在此，我们通过分析 和 菌株中GPA的产生水平，研究了 和 的CSRG之间的“串扰”，其中CSRG基因敲除通过异源CSRG的表达进行交叉互补。我们证明，尽管Tei15和Dbv4 StrR样PSR是直系同源的，但它们并非完全可互换： 和 仅部分能够或无法交叉互补 在 和 中敲除的 。 在 中敲除 ，这意味着这些PSR的DNA结合特性比之前认为的差异更大。同时，不相关的LuxR样PSR Tei16和Dbv3能够交叉互补在 和 中敲除的相应 。此外， 在 中的异源表达导致替考拉宁产量显著增加。尽管这些事件的分子背景值得进一步研究，但我们的结果有助于更深入地理解GPA生物合成调控，并提供新的生物技术工具来提高其产量。
