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Genetic insights into the mechanism of teicoplanin self-resistance in Actinoplanes teichomyceticus.
The Journal of Antibiotics ( IF 2.1 ) Pub Date : 2020-01-17 , DOI: 10.1038/s41429-019-0274-9 Oleksandr Yushchuk 1 , Vitalina Homoniuk 1 , Bohdan Ostash 1 , Flavia Marinelli 2 , Victor Fedorenko 1
The Journal of Antibiotics ( IF 2.1 ) Pub Date : 2020-01-17 , DOI: 10.1038/s41429-019-0274-9 Oleksandr Yushchuk 1 , Vitalina Homoniuk 1 , Bohdan Ostash 1 , Flavia Marinelli 2 , Victor Fedorenko 1
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Actinoplanes teichomyceticus NRRL B-16726 is the only known producer of the clinically important glycopeptide antibiotic teicoplanin. The producing strain is highly self-resistant to teicoplanin. Although the biosynthesis of teicoplanin has been investigated, much of our understanding of self-resistance in the producing strain is based on the extrapolation of existing data about glycopeptide resistance (mediated by the expression of vanRS-vanHAX genes) in other actinomycetes and cocci. The organization of the operons carrying putative van orthologues in A. teichomyceticus differs from known precedents, further adding up to the uncertainty about teicoplanin self-resistance mechanisms. Here, we determined operon structure of the teicoplanin resistance genes in A. teichomyceticus. Although Tei15* is necessary to activate teicoplanin biosynthetic genes, the expression of van orthologues was shown to be independent of Tei15*. We further showed that tei7 promoter driving the expression of vanHAX orthologues is dependent on Tei2 (VanR). Finally, we demonstrate the utility of the tei2 promoter as a new tool to achieve strong constitutive expression in A. teichomyceticus.
中文翻译：
放线放线菌teichomyceticus中替考拉宁自我抗性机制的遗传学见解。
放线猕猴菌NRRL B-16726是临床上重要的糖肽抗生素替考拉宁的唯一已知生产者。产生菌株对替考拉宁具有高度自我抗性。尽管已经研究了替考拉宁的生物合成，但我们对生产菌株中自抗性的许多理解是基于对其他放线菌和球菌中糖肽耐药性（由vanRS-vanHAX基因表达介导的）现有数据的推断。teichomyceticus中携带推定的范直向同源物的操纵子的组织不同于已知的先例，进一步加重了teicoplanin自耐药机制的不确定性。在这里，我们确定了teichomyceticus中的teicoplanin抗性基因的操纵子结构。尽管Tei15 *是激活teicoplanin生物合成基因所必需的，但显示出Van直向同源物的表达独立于Tei15 *。我们进一步表明，驱动vanHAX直向同源物表达的tei7启动子依赖于Tei2（VanR）。最后，我们证明了tei2启动子的实用性，作为一种新的工具，可在teichomyceticus中实现强大的组成型表达。
更新日期：2020-01-17
中文翻译：
放线放线菌teichomyceticus中替考拉宁自我抗性机制的遗传学见解。
放线猕猴菌NRRL B-16726是临床上重要的糖肽抗生素替考拉宁的唯一已知生产者。产生菌株对替考拉宁具有高度自我抗性。尽管已经研究了替考拉宁的生物合成，但我们对生产菌株中自抗性的许多理解是基于对其他放线菌和球菌中糖肽耐药性（由vanRS-vanHAX基因表达介导的）现有数据的推断。teichomyceticus中携带推定的范直向同源物的操纵子的组织不同于已知的先例，进一步加重了teicoplanin自耐药机制的不确定性。在这里，我们确定了teichomyceticus中的teicoplanin抗性基因的操纵子结构。尽管Tei15 *是激活teicoplanin生物合成基因所必需的，但显示出Van直向同源物的表达独立于Tei15 *。我们进一步表明，驱动vanHAX直向同源物表达的tei7启动子依赖于Tei2（VanR）。最后，我们证明了tei2启动子的实用性，作为一种新的工具，可在teichomyceticus中实现强大的组成型表达。
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