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Antibacterial activity and carbapenem re‐sensitizing ability of 1,10‐phenanthroline‐5,6‐dione and its metal complexes against KPC‐producing Klebsiella pneumoniae clinical strains

Infections caused by KPC‐producing Klebsiella pneumoniae (Kp‐KPC) are associated with high mortality rates due to the increased number of resistant isolates and the scarcity of therapeutic options. This scenario reinforces the urgent need for new chemotherapeutics. Herein, we investigated the effects of 1,10‐phenanthroline‐5,6‐dione (phendione) and its metal‐based complexes, [Cu(phendione)3](ClO4)2.4H2O (Cu–phendione) and [Ag(phendione)2]ClO4 (Ag–phendione), both alone and also combined with carbapenems (meropenem (MEM), and imipenem), against 46 clonally distinct clinical strains of Kp‐KPC. All isolates were found to be multidrug resistant in accordance with their susceptibility patterns by disk diffusion method. Compounds geometric mean (GM)‐MIC and GM‐MBC values (μmol l−1), respectively, were: phendione, 42·06 and 71·27; Cu–phendione, 9·88 and 13·75; and Ag–phendione, 10·10 and 13·06. Higher synergism rates of MEM‐containing combinations were observed by the checkerboard assay, particularly with the two metal complexes. Moreover, drug combinations were able to re‐sensitize 87% of the phenotypically non‐susceptible strains. Time‐kill studies, with MEM plus Cu–phendione or Ag–phendione, indicated that combinations with 0·5× MIC of each agent produce synergistic effects after 9–12 h. The MEM plus Ag–phendione eradicated about 106 CFU per ml of bacteria. These findings support the effectiveness of the re‐sensitizing combinatorial approach and provide evidence that phendione‐based compounds offer real promise in the fight against Kp‐KPC infections.