Copper ions and coordination complexes as novel carbapenem adjuvants.

Abstract

Carbapenem-resistant Enterobacteriaceae are an urgent threat to global human health. These organisms produce ß-lactamases with carbapenemase activity, such as the metallo-ß-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 ß-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 ß-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.

Authors 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; Mitic, NataĊĦa; Walsh, Timothy R; Anderson, Gregory J; Shafer, William M; Paterson, David L; Schenk, Gerhard; McEwan, Alastair G; Schembri, Mark A
Journal ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Pages
Volume 62
Date 1/11/2017
Grant ID GNT1033799
Funding Body National Health and Medical Research Council (NHMRC) of Australia
URL http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1128/AAC.02280-17