The human microbiome encodes resistance to the antidiabetic drug acarbose

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, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Acarbose / metabolism
  • Acarbose / pharmacology*
  • Amylases / metabolism
  • Animals
  • Drug Resistance, Bacterial / drug effects*
  • Gastrointestinal Microbiome / drug effects*
  • Humans
  • Hypoglycemic Agents / metabolism
  • Hypoglycemic Agents / pharmacology*
  • Inactivation, Metabolic*
  • Metagenome / drug effects
  • Metagenome / genetics*
  • Models, Molecular
  • Mouth / drug effects
  • Mouth / microbiology*
  • Phosphotransferases (Alcohol Group Acceptor) / chemistry
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism


  • Hypoglycemic Agents
  • Phosphotransferases (Alcohol Group Acceptor)
  • acarbose 7-phosphotransferase
  • Amylases
  • Acarbose