Nature:阿卡波糖降糖不理想?有菌群酶让药失活
  • 搜索人宏基因组数据+生化测试,鉴定出多个菌群编码的阿卡波糖激酶(Mak)基因;
  • Mak基因广泛存在于口腔菌群,肠道菌群中也有一些;
  • 对其中一种酶Mak1做酶动力学和晶体结构分析,发现该酶通过与已知阿卡波糖激酶AcbK相似的机制,特异性地使阿卡波糖磷酸化,致其失活;
  • 表达Mak1的工程菌能抵抗阿卡波糖对其生长的抑制作用;
  • 分析已发表RCT数据发现,菌群中存在Mak基因的糖尿病患者对阿卡波糖的治疗应答较弱;
  • 一种口腔放线菌可产生内源性阿卡波糖样分子,或能解释为何Mak基因在人微生物组中普遍存在。
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mildbreeze
阿卡波糖源自土壤细菌,能通过抑制α-葡糖苷酶来减少生物体对复杂碳水化合物的代谢。这一作用机制使得阿卡波糖被开发为抗糖尿病药,能改善患者的餐后血糖。但阿卡波糖也会抑制细菌的α-葡糖苷酶,从而对人体菌群造成影响。那么人类微生物组中是否也存在抵抗阿卡波糖的机制呢?为了解答这一问题,美国普林斯顿大学Mohamed S. Donia作为通讯作者,与罗格斯大学、上海交通大学的赵立平团队合作,通过宏基因组学、生化和结构生物学方法,找到了在人体菌群中广泛存在的能让阿卡波糖失活的细菌酶(Maks),并通过分析已发表的临床试验数据(查看文章),初步证实了这类酶可能是削弱阿卡波糖对糖尿病治疗效果的“罪魁祸首”。该研究还进一步找到了能生成阿卡波糖样分子的人类口腔细菌,提示Maks可能是人体菌群抵抗这种内源性阿卡波糖的适应性策略。总之,该研究为菌群-药物互作提供了又一个范式,或能在临床上指导糖尿病患者用药。相关成果已在Nature发表,值得专业人士关注。
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Nature [IF:49.962]

The human microbiome encodes resistance to the antidiabetic drug acarbose

人类微生物组编码对抗糖尿病药物阿卡波糖的抗性

10.1038/s41586-021-04091-0

2021-11-24, Article

Abstract & Authors:展开

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The human microbiome encodes a large repertoire of biochemical enzymes and pathways, most of which remain uncharacterized. Here, using a metagenomics-based search strategy, we discovered that bacterial members of the human gut and oral microbiome encode enzymes that selectively phosphorylate a clinically used antidiabetic drug, acarbose1,2, resulting in its inactivation. Acarbose is an inhibitor of both human and bacterial α-glucosidases3, limiting the ability of the target organism to metabolize complex carbohydrates. Using biochemical assays, X-ray crystallography and metagenomic analyses, we show that microbiome-derived acarbose kinases are specific for acarbose, provide their harbouring organism with a protective advantage against the activity of acarbose, and are widespread in the microbiomes of western and non-western human populations. These results provide an example of widespread microbiome resistance to a non-antibiotic drug, and suggest that acarbose resistance has disseminated in the human microbiome as a defensive strategy against a potential endogenous producer of a closely related molecule.

First Authors:
Jared Balaich

Correspondence Authors:
Mohamed S Donia

All Authors:
Jared Balaich,Michael Estrella,Guojun Wu,Philip D Jeffrey,Abhishek Biswas,Liping Zhao,Alexei Korennykh,Mohamed S Donia

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肠菌与健康微信公众号

降糖药无效?可能是被肠道菌给吃掉了

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生物医学科研之家微信公众号

Nature:菌群酶让阿卡波糖药性失活

2021-11-28

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