Antimitotic rhizoxin derivatives from a cultured bacterial endosymbiont of the rice pathogenic fungus Rhizopus microsporus
Antimitotic rhizoxin derivatives from a cultured bacterial endosymbiont of the rice pathogenic fungus Rhizopus microsporus
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DOI：
10.1021/ja062953o
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发表时间：
2006-09-06
影响因子：
15
通讯作者：
Hertweck, Christian
中科院分区：
文献类型：
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作者：
Scherlach, Kirstin;Partida-Martinez, Laila P.;Hertweck, Christian
20多年来，人们一直认为水稻幼苗枯萎病的病原菌不是由小孢子菌产生的，而是由真菌菌丝体内的内生细菌产生的。本文报道了细菌内共生菌(“Burkholderia Rhoxina”)的成功分离和在纯培养条件下的大规模发酵，从而显著提高了抗真菌药物的产量(10倍以上)。除了几个已知的根毒素衍生物外，还分离出了许多新的天然和半合成变异体，并对它们的结构进行了全面的阐明。基于细胞的分析以及微管蛋白结合实验表明，甲基化的次根霉毒素衍生物的活性是根霉毒素的1000-10000倍，因此是迄今已知的最有效的抗增殖剂之一。此外，通过有效地抑制参与大环内酯类剪裁的可能的P-450单加氧酶，可以获得更稳定的二脱环氧根毒素类似物。
The potent antimitotic polyketide macrolide rhizoxin, the causal agent of rice seedling blight, is not produced by the fungus Rhizopus microsporus, as has been believed for over two decades, but by endosymbiotic bacteria that reside within the fungal mycelium. Here we report the successful isolation and large-scale fermentation of the bacterial endosymbiont ("Burkholderia rhizoxina") in pure culture, which resulted in a significantly elevated (10 x higher) production of antimitotics. In addition to several known rhizoxin derivatives, numerous novel natural and semisynthetic variants were isolated, and their structures were fully elucidated. Cell-based assays as well as tubulin binding experiments revealed that methylated seco-rhizoxin derivatives are 1000-10000 times more active than rhizoxin and thus rank among the most potent antiproliferative agents known to date. Furthermore, more stable didesepoxy rhizoxin analogues were obtained by efficiently inhibiting a putative P-450 monooxygenase involved in macrolide tailoring.