Version 1
: Received: 11 July 2024 / Approved: 11 July 2024 / Online: 11 July 2024 (04:52:41 CEST)
How to cite:
Joshi, P.; Krco, S.; Davis, S. J.; Asser, L.; Brück, T.; Soo, R. M.; Bodén, M.; Hugenholtz, P.; Wilson, L. A.; Schenk, G.; Morris, M. T. Phage Anti-Pycsar Proteins Efficiently Degrade β-Lactam Antibiotics. Preprints2024, 2024070921. https://doi.org/10.20944/preprints202407.0921.v1
Joshi, P.; Krco, S.; Davis, S. J.; Asser, L.; Brück, T.; Soo, R. M.; Bodén, M.; Hugenholtz, P.; Wilson, L. A.; Schenk, G.; Morris, M. T. Phage Anti-Pycsar Proteins Efficiently Degrade β-Lactam Antibiotics. Preprints 2024, 2024070921. https://doi.org/10.20944/preprints202407.0921.v1
Joshi, P.; Krco, S.; Davis, S. J.; Asser, L.; Brück, T.; Soo, R. M.; Bodén, M.; Hugenholtz, P.; Wilson, L. A.; Schenk, G.; Morris, M. T. Phage Anti-Pycsar Proteins Efficiently Degrade β-Lactam Antibiotics. Preprints2024, 2024070921. https://doi.org/10.20944/preprints202407.0921.v1
APA Style
Joshi, P., Krco, S., Davis, S. J., Asser, L., Brück, T., Soo, R. M., Bodén, M., Hugenholtz, P., Wilson, L. A., Schenk, G., & Morris, M. T. (2024). Phage Anti-Pycsar Proteins Efficiently Degrade β-Lactam Antibiotics. Preprints. https://doi.org/10.20944/preprints202407.0921.v1
Chicago/Turabian Style
Joshi, P., Gerhard Schenk and Marc T Morris. 2024 "Phage Anti-Pycsar Proteins Efficiently Degrade β-Lactam Antibiotics" Preprints. https://doi.org/10.20944/preprints202407.0921.v1
Abstract
Metallo-β-lactamases (MBLs) are members of the structurally conserved but functionally diverse MBL-fold superfamily of metallohydrolases. MBLs are a major concern for global health care as they efficiently inactivate β-lactam antibiotics, including the “last-resort” carbapenems, and no clinically suitable inhibitors are currently available. Increasingly, promiscuous β-lactamase activity is also observed in other members of the superfamily, including from viruses, which represents an underexplored reservoir for future pathways to antibiotic resistance. Here, two such MBL-fold enzymes from Bacillus phages, the cyclic mononucleotide-degrading proteins ApycGoe3 and ApycGrass, are shown to efficiently degrade β-lactam substrates in vitro. In particular, ApycGrass displays a distinct preference for carbapenem substrates with a catalytic efficiency that is within one order of magnitude of that of the clinically relevant MBL NDM-1. Mutagenesis experiments also demonstrate that the loss of a metal-bridging aspartate residue reduces nuclease activity up to 35-fold, but improves carbapenemase activity. In addition, we propose that the oligomeric state significantly influences β-lactamase activity by modifying access to the active site pocket. Together, these observations hint at a possible new avenue of resistance via the spread of phage-borne MBL-fold enzymes with β-lactamase activity.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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