Copper Ions and Coordination Complexes as Novel Carbapenem Adjuvants

• Published in: Antimicrobial agents and chemotherapy 2018-02, Vol.62 (2)
• Main 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 E, 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
• Format: Article
• Language: English
• Subjects: Adjuvants, Pharmaceutic; Coordination Complexes; Copper; Experimental Therapeutics; Ions
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02280-17

Carbapenem-resistant are urgent threats 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 isolate, MS6192, was cultured from the urine of a patient with a urinary tract infection. MS6192 was resistant to antibiotics from multiple classes, including diverse β-lactams (penicillins, cephalosporins, and carbapenems), aminoglycosides, and fluoroquinolones. In the presence of copper (range, 0 to 2 mM), however, the susceptibility of MS6192 to the carbapenems ertapenem and meropenem increased markedly. In standard checkerboard assays, copper decreased the MICs 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 gene from MS6192 was cloned and expressed in a recombinant K-12 strain. Analysis of cell extracts prepared from this strain revealed that copper directly inhibited NDM-1 activity, which was confirmed using purified recombinant NDM-1. Finally, delivery of copper at a low concentration of 10 μM by using the FDA-approved coordination complex copper-pyrithione sensitized MS6192 to ertapenem and meropenem in a synergistic manner. Overall, this work demonstrates the potential use of copper coordination complexes as novel carbapenemase adjuvants.