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Copper ions and coordination complexes as novel carbapenem adjuvants

Djoko, Karrera Y.; Achard, Maud E.S.; Phan, Minh-Duy; Lo, Alvin W.; Miraula, Manfredi; Prombhul, Sasiprapa; Hancock, Steven J.; Peters, Kate M.; Sidjabat, Hanna; Harris, Patrick N.; Mitić, Nataša; Walsh, Timothy R.; Anderson, Gregory J.; Shafer, William M.; Paterson, David L.; Schenk, Gerhard; McEwan, Alastair G.; Schembri, Mark A.

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Authors

Maud E.S. Achard

Minh-Duy Phan

Alvin W. Lo

Manfredi Miraula

Sasiprapa Prombhul

Steven J. Hancock

Kate M. Peters

Hanna Sidjabat

Patrick N. Harris

Nataša Mitić

Timothy R. Walsh

Gregory J. Anderson

William M. Shafer

David L. Paterson

Gerhard Schenk

Alastair G. McEwan

Mark A. Schembri



Abstract

Carbapenem-resistant Enterobacteriaceae are an urgent threat to global human health. These organisms produce β-lactamases with carbapenemase activity, such as the metallo-β-lactamase NDM-1, which is notable due to its association with mobile genetic elements and the lack of a clinically useful inhibitor. Here we examined the ability of copper to inhibit the activity of NDM-1 and explored the potential of a copper coordination complex as a mechanism to efficiently deliver copper as an adjuvant in clinical therapeutics. An NDM-positive Escherichia coli isolate, MS6192, was cultured from the urine of a patient with urinary tract infection. MS6192 was resistant to antibiotics from multiple classes, including diverse β-lactams (penicillins, cephalosporins, and carbapenems), aminoglycosides and fluoroquinolones. However, in the presence of copper (range 0-2 mM), the susceptibility of MS6192 to the carbapenems ertapenem and meropenem increased significantly. In standard checkerboard assays, copper decreased the MIC of ertapenem and meropenem against MS6192 in a dose-dependent manner, suggesting a synergistic mode of action. To examine the inhibitory effect of copper in the absence of other β-lactamases, the blaNDM-1 gene from MS6192 was cloned and expressed in a recombinant E. coli K-12 strain. Analysis of cell-free extracts prepared from this strain revealed copper directly inhibits NDM-1 activity, and this was further confirmed using purified recombinant NDM-1. Finally, delivery of copper at a low concentration of 10 μM using the FDA-approved coordination complex copper-pyrithione sensitised MS6192 to ertapenem and meropenem in a synergistic manner. Overall, this work demonstrates the potential use of copper-coordination complexes as novel carbapenemase adjuvants.

Citation

Djoko, K. Y., Achard, M. E., Phan, M., Lo, A. W., Miraula, M., Prombhul, S., …Schembri, M. A. (2018). Copper ions and coordination complexes as novel carbapenem adjuvants. Antimicrobial Agents and Chemotherapy, 62(2), e02280-17. https://doi.org/10.1128/aac.02280-17

Journal Article Type Article
Acceptance Date Nov 6, 2017
Online Publication Date Jan 25, 2018
Publication Date Feb 1, 2018
Deposit Date Nov 22, 2017
Publicly Available Date Aug 1, 2018
Journal Antimicrobial Agents and Chemotherapy
Print ISSN 0066-4804
Electronic ISSN 1098-6596
Publisher American Society for Microbiology
Peer Reviewed Peer Reviewed
Volume 62
Issue 2
Article Number e02280-17
Pages e02280-17
DOI https://doi.org/10.1128/aac.02280-17

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