The enediynes, microbial natural products with extraordinary cytotoxicities, have been translated into clinical drugs. Two self-resistance mechanisms are known in the enediyne producers—apoproteins for the nine-membered enediynes and self-sacrifice proteins for the ten-membered enediyne calicheamicin. Here we show that: (1)tnmS1,tnmS2, andtnmS3encode tiancimycin (TNM) resistance in its producerStreptomycessp. CB03234, (2)tnmS1,tnmS2, andtnmS3homologs are found in all anthraquinone-fused enediyne producers, (3) TnmS1, TnmS2, and TnmS3 share a similar β barrel-like structure, bind TNMs with nanomolarKDvalues, and confer resistance by sequestration, and (4) TnmS1, TnmS2, and TnmS3 homologs are widespread in nature, including in the human microbiome. These findings unveil an unprecedented resistance mechanism for the enediynes. Mechanisms of self-resistance in producers serve as models to predict and combat future drug resistance in clinical settings. Enediyne-based chemotherapies should now consider the fact that the human microbiome harbors genes encoding enediyne resistance.

中文翻译：

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螯合对Enediyne抗肿瘤抗生素的耐药性

烯二炔，具有非凡的细胞毒性的微生物天然产物，已被转化为临床药物。烯二炔生产者中已知两种自我抗性机制：九元烯二炔的载脂蛋白和十元烯二酮加利车霉素的自我牺牲蛋白。在这里，我们显示：（1）tnmS1，tnmS2和tnmS3编码其生产者Streptomycessp中的tiancimycin（TNM）耐药性。CB03234，（2）tnmS1，tnmS2和tnmS3同源物存在于所有蒽醌融合的二炔生产商中，（3）TnmS1，TnmS2和TnmS3具有相似的β桶状结构，将TNM与nanomolarKD值结合，并通过螯合赋予抗性，并（4）TnmS1，TnmS2和TnmS3同源物在自然界很广泛，包括在人类微生物组中。这些发现揭示了对双烯类化合物前所未有的抵抗机制。生产者的自我抗药性机制可作为预测和对抗临床环境中未来抗药性的模型。基于Enediyne的化学疗法现在应该考虑这样一个事实，即人类微生物组具有编码Endiedyne耐药性的基因。