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

Abstract

Gut microbiota plays an important role in drug modi cation, transformation and degradation, which are factors that need to be considered in personalized therapy. Acarbose, an inhibitor of α-glucosidase, is used as a rst-line drug for the treatment of type 2 diabetes; however, its clinical effects vary greatly among individuals, and the underlying mechanisms relating to the contribution of gut microbes remain to be elucidated. Herein, we reported the association between acarbose resistance and enteric bacteria by analyzing clinical samples and anaerobic enrichment culture, and isolated a major acarbose-degrading gut strain, Klebsiella grimontii TD1. Metagenomic analysis of the intestinal microbiome found that the abundance of K. grimontii TD1 was higher in patients with weak acarbose response and increased with longer medication time. In addition, in vivo experiments using a diabetic mouse model showed that this strain signi cantly weakened the hypoglycemic effect of acarbose. Further, we identi ed a key acarbosepreferred glucosidase, Apg, in K. grimontiiTD1 using a combined approach of induced transcriptome and protein pro ling. This enzyme is structurally characteristic, could degrade acarbose into small molecules with loss of inhibitor function, and was widely distributed in intestinal microorganisms, especially in Klebsiella. These results indicate that the risk of acarbose resistance caused by metabolic degradation from intestinal bacteria is widespread in humans, and this "induced degradational inactivation" mechanism may be one of the main causes of non-antibiotic drug resistance. Full TextType 2 diabetes mellitus (T2DM) is a common chronic metabolic disease, and its incidence is increasing globally year by year 1 . Acarbose is a rst-line agent for the treatment of T2DM 2,3 ; however, clinical data

Discovery of a unique Ni2+-dependent heterohexameric metformin hydrolase

“…This raises concerns about whether metformin hydrolase may potentially be present in gut microbes, resultantly leading to the breakdown of the active prototype structure of metformin. A similar situation has been observed regarding acarbose, another antidiabetic drug, which is rendered inactive by enzymes present in the human gut and oral microbes 39,40 . Considering the signi cant secondary failure rate of metformin monotherapy in clinical practice 41 , the potential presence of metformin hydrolase in the human gut microbiome should be carefully investigated due to its implications for this important medication.…”

Functional metagenomic discovery of novel tetracycline and acarbose resistance genes from low biomass samples using METa assembly

“…For phylogenetic analysis of the putative tetracycline efflux pumps (TET1, TET3, and TET13), we downloaded CARD amino acid sequences 19,20 for the ontology term “major facilitator superfamily (MFS) antibiotic efflux pump” and added the functionally-selected efflux pump amino acid sequences to the FASTA file. For analysis of the predicted acarbose resistance proteins (ACA1 and ACA7), we compared them to sequences for the Klebsiella grimontii Apg enzyme and a Raoultella ornithinolytica α-glycosidase from the same manuscript 25 , additional reported acarbose degradation enzymes (maltogenic amylases from Thermus sp. IM6501, Geobacillus strearothermophilus , and a glycoside hydrolase from Lactiplantibacillus plantarum ) 26–29 , as well as acarbose phosphotransferases AcbK ( Actinoplanes sp.…”

“…Specifically, we investigated modification of acarbose (Figure 1D), a glucosidase inhibitor used in the treatment of diabetes 38,39 . Previous work has established that acarbose can be metabolized by bacteria in the human gut microbiome through modification by phosphorylation 30 and degradation [25][26][27][28][29]29,40 and that acarbose can prevent growth of E. coli when it is cultured with maltose as a sole carbon source 41 . This suggested to us that a functional metagenomic approach could be used to investigate acarbose metabolism.…”

Gut microbiome-derived hydrolases—an underrated target of natural product metabolism

“…Natural products such as flavonoids, lipids, saponins, and BAs have been found to have beneficial anti-diabetic properties ( Fan et al., 2023 ). Acarbose, a common antidiabetic medication, is subject to hydrolysis by K. grimontii TD1 bacteria in the human intestine, leading to potential resistance to acarbose ( Tian et al., 2023 ). The previous discussion focused on the relationship between natural product drugs and gut microbes, without delving into their specific role in diabetes.…”