Characterization of a highly efficient antibiotic-degrading metallo-β-lactamase obtained from an uncultured member of a permafrost community

Pedroso, Marcelo Monteiro, Selleck, Christopher, Enculescu, Charmaine, Harmer, Jeffrey R., Mitic, Natasa, Craig, Whitney R., Helweh, Waleed, Hugenholtz, Philip, Tyson, Gene W., Tierney, David L., Larrabee, James A. and Schenk, Gerhard (2017) Characterization of a highly efficient antibiotic-degrading metallo-β-lactamase obtained from an uncultured member of a permafrost community. Metallomics, 9 8: 1157-1168. doi:10.1039/c7mt00195a


Author Pedroso, Marcelo Monteiro
Selleck, Christopher
Enculescu, Charmaine
Harmer, Jeffrey R.
Mitic, Natasa
Craig, Whitney R.
Helweh, Waleed
Hugenholtz, Philip
Tyson, Gene W.
Tierney, David L.
Larrabee, James A.
Schenk, Gerhard
Title Characterization of a highly efficient antibiotic-degrading metallo-β-lactamase obtained from an uncultured member of a permafrost community
Journal name Metallomics   Check publisher's open access policy
ISSN 1756-591X
1756-5901
Publication date 2017-08-01
Year available 2017
Sub-type Article (original research)
DOI 10.1039/c7mt00195a
Open Access Status Not yet assessed
Volume 9
Issue 8
Start page 1157
End page 1168
Total pages 12
Place of publication Cambridge, United Kingdom
Publisher Royal Society of Chemistry
Language eng
Subject 1601 Chemistry (miscellaneous)
1304 Biophysics
2502 Biomaterials
1303 Biochemistry
2506 Metals and Alloys
Abstract Antibiotic resistance is a major global health problem, one that threatens to derail the benefits garnered from arguably the greatest success of modern medicine, the discovery of antibiotics. Among the most potent agents contributing to antibiotic resistance are metallo-beta-lactamases (MBLs). The discovery of MBL-like enzymes in microorganisms that are not in contact with the human population is of particular concern as these proteins already have the in-built capacity to inactivate antibiotics, even though they may not need MBL activity for their survival. Here, we demonstrate that a microbiome from a remote and frozen environment in Alaska harbours at least one highly efficient MBL, LRA-8. LRA-8 is homologous to the B3 subgroup of MBLs and has a substrate profile and catalytic properties similar to well-known members of this enzyme family, which are expressed by major human pathogens. LRA-8 is predominantly a penicillinase, but is also active towards carbapenems, but not cephalosporins. Spectroscopic studies indicate that LRA-8 has an active site structure similar to that of other MBLs (in particular B3 subgroup representative AIM-1), and a combination of steady-state and pre-steady-state kinetic data demonstrate that the enzyme is likely to employ a metal ion-bridging hydroxide to initiate catalysis. The rate-limiting step is the decay of a chromophoric, tetrahedral intermediate, as is observed in various other MBLs. Thus, studying the properties of such "pristine'' MBL-like proteins may provide insight into the structural plasticity of this family of enzymes that may facilitate functional promiscuity, while important insight into the evolution of MBLs may also be gained.
Keyword Biochemistry & Molecular Biology
Biochemistry & Molecular Biology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1084778
DP150104358
CHE1303852
Institutional Status UQ

 
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