Natural tetracycline (TC) antibiotics were the first major class of therapeutics to earn the distinction of 'broad-spectrum antibiotics' and they have been used since the 1940s against a wide range of both Gram-positive and Gram-negative pathogens, mycoplasmas, intracellular chlamydiae, rickettsiae and protozoan parasites. The second generation of semisynthetic tetracyclines, such as minocycline and doxycycline, with improved antimicrobial potency, were introduced during the 1960s. Despite emerging resistance to TCs erupting during the 1980s, it was not until 2006, more than four decades later, that a third--generation TC, named tigecycline, was launched. In addition, two TC analogues, omadacycline and eravacycline, developed via (semi)synthetic and fully synthetic routes, respectively, are at present under clinical evaluation. Interestingly, despite very productive early work on the isolation of a Streptomyces aureofaciens mutant strain that produced 6-demethyl-7-chlortetracycline, the key intermediate in the production of second- and third-generation TCs, biosynthetic approaches in TC development have not been productive for more than 50 years. Relatively slow and tedious molecular biology approaches for the genetic manipulation of TC-producing actinobacteria, as well as an insufficient understanding of the enzymatic mechanisms involved in TC biosynthesis have significantly contributed to the low success of such biosynthetic engineering efforts. However, new opportunities in TC drug development have arisen thanks to a significant progress in the development of affordable and versatile biosynthetic engineering and synthetic biology approaches, and, importantly, to a much deeper understanding of TC biosynthesis, mostly gained over the last two decades.

中文翻译：

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链霉菌对土霉素的生物合成：四环素类抗生素开发的过去，现在和将来的方向。

天然四环素（TC）抗生素是第一类获得“广谱抗生素”殊荣的主要治疗方法，自1940年代以来，它们已被广泛用于革兰氏阳性和革兰氏阴性病原体，支原体，细胞内衣原体，立克次体和原生动物寄生虫。1960年代引入了第二代半合成四环素，例如米诺环素和强力霉素，具有增强的抗菌效力。尽管在1980年代对TC爆发了新的抵抗力，但直到2006年，才过了40年，才推出了第三代TC，名为tigecycline。此外，通过TC开发了两种TC类似物omadacycline和eravacycline 。（半）合成和完全合成途径，目前正在临床评估中。有趣的是，尽管在分离金黄色链霉菌方面的早期研究成果卓著，产生6-脱甲基-7-氯四环素（第二代和第三代TC生产的关键中间体）的突变菌株，TC开发中的生物合成方法生产已超过50年。产生TC的放线菌的遗传操作的相对缓慢而乏味的分子生物学方法，以及对TC生物合成中涉及的酶促机制的不充分了解，极大地导致了此类生物合成工程努力的低成功。但是，得益于可负担得起的多功能生物合成工程和合成生物学方法的发展，以及重要的是，对TC生物合成的更深入的了解（主要是在过去的二十年间），TC药物开发出现了新的机遇。