TY - JOUR
T1 - The human microbiome encodes resistance to the antidiabetic drug acarbose
AU - Balaich, Jared
AU - Estrella, Michael
AU - Wu, Guojun
AU - Jeffrey, Philip D.
AU - Biswas, Abhishek
AU - Zhao, Liping
AU - Korennykh, Alexei
AU - Donia, Mohamed S.
N1 - Funding Information:
Acknowledgements We thank the NSLS-2 AMX and FMX beamline staff for their assistance with data collection and the crystallography core facility at the Department of Molecular Biology, Princeton University. We thank M. Cahn and M. Elmassry for assistance with metagenomic data analysis; S. Chatterjee for general assistance; and the rest of the Donia laboratory for discussions. Funding for this project was provided by an NIH Director’s New Innovator Award (1DP2AI124441) and the Pew Biomedical Scholars Program to M.S.D.; an NIH grant (1R01GM110161), a Burroughs Wellcome Foundation Grant (1013579) and an award from The Vallee Foundation to A.K. J.B. is funded by a training grant from the National Institute of General Medicine Sciences (NIGMS) (T32GM007388) and L.Z. is a CIFAR fellow. This research used the AMX and FMX beamlines of the National Synchrotron Light Source II, a United States Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Brookhaven National Laboratory under contract no. DE-SC0012704. The Life Science Biomedical Technology Research resource, which supports AMX and FMX, is primarily supported by the NIH (NIGMS) through a Biomedical Technology Research Resource P41 grant (P41GM111244), and by the DOE Office of Biological and Environmental Research (KP1605010).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/12/2
Y1 - 2021/12/2
N2 - 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.
AB - 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.
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U2 - 10.1038/s41586-021-04091-0
DO - 10.1038/s41586-021-04091-0
M3 - Article
C2 - 34819672
AN - SCOPUS:85120922721
SN - 0028-0836
VL - 600
SP - 110
EP - 115
JO - Nature
JF - Nature
IS - 7887
ER -