The human microbiome encodes resistance to the antidiabetic drug acarbose

Jared Balaich, Michael Estrella, Guojun Wu, Philip D. Jeffrey, Abhishek Biswas, Liping Zhao, Alexei Korennykh and Mohamed S. Donia ()
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Jared Balaich: Princeton University
Michael Estrella: Princeton University
Guojun Wu: Rutgers University
Philip D. Jeffrey: Princeton University
Abhishek Biswas: Princeton University
Liping Zhao: Rutgers University
Alexei Korennykh: Princeton University
Mohamed S. Donia: Princeton University

Nature, 2021, vol. 600, issue 7887, 110-115

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-04091-0

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