The human microbiome encodes resistance to the antidiabetic drug acarbose.

TitleThe human microbiome encodes resistance to the antidiabetic drug acarbose.
Publication TypeJournal Article
Year of Publication2021
AuthorsBalaich, J, Estrella, M, Wu, G, Jeffrey, PD, Biswas, A, Zhao, L, Korennykh, A, Donia, MS
JournalNature
Volume600
Issue7887
Pagination110-115
Date Published2021 12
ISSN1476-4687
KeywordsAcarbose, Amylases, Animals, Drug Resistance, Bacterial, Gastrointestinal Microbiome, Humans, Hypoglycemic Agents, Inactivation, Metabolic, Metagenome, Models, Molecular, Mouth, Phosphotransferases (Alcohol Group Acceptor)
Abstract

<p>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.</p>

DOI10.1038/s41586-021-04091-0
Alternate JournalNature
PubMed ID34819672
Grant ListR01 GM110161 / GM / NIGMS NIH HHS / United States
T32 GM007388 / GM / NIGMS NIH HHS / United States
1013579 / WT_ / Wellcome Trust / United Kingdom
DP2 AI124441 / AI / NIAID NIH HHS / United States
P41 GM111244 / GM / NIGMS NIH HHS / United States