Inactivation of the antidiabetic drug acarbose by human intestinal microbial-mediated degradation

Drugs can be modified or degraded by the gut microbiota, which needs to be considered in personalized therapy. The clinical efficacy of the antidiabetic drug acarbose, an inhibitor of α-glucosidase, varies greatly among individuals for reasons that are largely unknown. Here we identify in the human gut acarbose-degrading bacteria, termed Klebsiella grimontii TD1, whose presence is associated with acarbose resistance in patients. Metagenomic analyses reveal that the abundance of K. grimontii TD1 is higher in patients with a weak response to acarbose and increases over time with acarbose treatment. In male diabetic mice, co-administration of K. grimontii TD1 reduces the hypoglycaemic effect of acarbose. Using induced transcriptome and protein profiling, we further identify an acarbose preferred glucosidase, Apg, in K. grimontii TD1, which can degrade acarbose into small molecules with loss of inhibitor function and is widely distributed in human intestinal microorganisms, especially in Klebsiella . Our results suggest that a comparatively large group of individuals could be at risk of acarbose resistance due to its degradation by intestinal bacteria, which may represent a clinically relevant example of non-antibiotic drug resistance. The antidiabetic drug acarbose is shown to be degraded by a Klebsiella species present in the human gut, which is enriched with acarbose treatment and might mediate acarbose resistance and variations in clinical efficacy observed in patients.