Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
Center for Microbiome, Nutrition, and Health, New Jersey Institute for Food, Nutrition, and Health, Department of Biochemistry and Microbiology, Rutgers University, New Brunswick, NJ, USA.
Nature. 2021 Dec;600(7887):110-115. doi: 10.1038/s41586-021-04091-0. Epub 2021 Nov 24.
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, acarbose, resulting in its inactivation. Acarbose is an inhibitor of both human and bacterial α-glucosidases, 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.
人类微生物组编码了大量的生化酶和途径，其中大多数仍未被描述。在这里，我们使用基于宏基因组学的搜索策略，发现人类肠道和口腔微生物组中的细菌成员编码的酶能够选择性地上调一种临床使用的抗糖尿病药物阿卡波糖，导致其失活。阿卡波糖是人和细菌α-葡萄糖苷酶的抑制剂，限制了靶生物代谢复杂碳水化合物的能力。通过生化分析、X 射线晶体学和宏基因组学分析，我们表明微生物组衍生的阿卡波糖激酶对阿卡波糖具有特异性，为其宿主提供了对阿卡波糖活性的保护优势，并且在西方和非西方人群的微生物组中广泛存在。这些结果提供了一个广泛的微生物组对非抗生素药物产生耐药性的例子，并表明阿卡波糖耐药性已经作为一种针对潜在内源性密切相关分子产生的防御策略在人类微生物组中传播。
