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. ![]() |
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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.
Item Type: | Article |
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Date Type: | Published Online |
Status: | Published |
Schools: | Schools > Medicine |
Publisher: | American Society for Microbiology |
ISSN: | 0066-4804 |
Date of First Compliant Deposit: | 4 December 2017 |
Date of Acceptance: | 6 November 2017 |
Last Modified: | 23 Nov 2024 01:15 |
URI: | https://orca.cardiff.ac.uk/id/eprint/107255 |
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