Identification of novel tylosin analogues generated by a wblA disruption mutant of Streptomyces ansochromogenes.
Identification of novel tylosin analogues generated by a wblA disruption mutant of Streptomyces ansochromogenes.
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产色链霉菌 wblA 破坏突变体产生的新型泰乐菌素类似物的鉴定
DOI：
10.1186/s12934-015-0359-5
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发表时间：
2015-11-02
影响因子：
6.4
通讯作者：
Tan H
中科院分区：
文献类型：
--
作者：
Lu C;Liao G;Zhang J;Tan H
背景：链霉菌作为抗生素的主要来源，已被广泛用于发现新的候选药物来对抗不断进化的病原体。 wblA（一种控制主要发育转变的放线菌特异性基因）的破坏可导致许多链霉菌属表型和形态的改变。通过使用基本局部比对搜索工具，在 Streptomyces ansochromogenes 7100 中发现了一个 wblA 同源物。确定 wblA 破坏突变体是否可以产生新的次生代谢产物是很有趣的，正如其他链霉菌中所证明的那样。结果：通过同源重组构建了 S. ansochromogenes 7100 (ΔwblA) 的 wblA 破坏突变体。 ΔwblA 未能产生孢子和尼可霉素，这是 S. ansochromogenes 7100（野生型菌株）在发酵过程中的主要产物。使用ΔwblA发酵液观察到对金黄色葡萄球菌和蜡样芽孢杆菌的抗菌活性，但对野生型菌株没有观察到抗菌活性。为了鉴定抗菌化合物，通过质谱和核磁共振波谱将ΔwblA产生的两种化合物（化合物1和化合物2）定性为16元大环内酯。这些化合物的化学结构与泰乐菌素相似，生物测定表明这两种化合物可抑制多种革兰氏阳性菌的生长。有趣的是，它们对肺炎链球菌的活性比泰乐菌素高得多。结论：ΔwblA 产生了两种新型泰乐菌素类似物（化合物 1 和 2）。生物测定表明，化合物1和2对肺炎链球菌的活性比泰乐菌素高得多，这意味着这两种化合物可能用于拓宽泰乐菌素的应用。
Background:Streptomyces, as the main source of antibiotics, has been intensively exploited for discovering new drug candidates to combat the evolving pathogens. Disruption of wblA, an actinobacteria-specific gene controlling major developmental transition, can cause the alteration of phenotype and morphology in many species of Streptomyces. One wblA homologue was found in Streptomyces ansochromogenes 7100 by using the Basic Local Alignment Search Tool. It is interesting to identify whether novel secondary metabolites could be produced by the wblA disruption mutant as evidenced in other Streptomyces.Results:The wblA disruption mutant of S. ansochromogenes 7100 (ΔwblA) was constructed by homologous recombination. ΔwblA failed to produce spores and nikkomycin, the major product of S. ansochromogenes 7100 (wild-type strain) during fermentation. Antibacterial activity against Staphylococcus aureus and Bacillus cereus was observed with fermentation broth of ΔwblA but not with that of the wild-type strain. To identify the antibacterial compounds, the two compounds (compound 1 and compound 2) produced by ΔwblA were characterized as 16-membered macrolides by mass spectrometry and nuclear magnetic resonance spectroscopy. The chemical structure of these compounds shows similarity with tylosin, and the bioassays indicated that the two compounds inhibited the growth of a number of gram-positive bacteria. It is intriguing that they displayed much higher activity than tylosin against Streptococcus pneumoniae.Conclusions:Two novel tylosin analogues (compound 1 and 2) were generated by ΔwblA. Bioassays showed that compound 1 and 2 displayed much higher activity than tylosin against Streptococcus pneumoniae, implying that these two compounds might be used to widen the application of tylosin.