Bismuth complex of quinoline thiosemicarbazone restores carbapenem sensitivity in NDM-1-positive Klebsiella pneumoniae

Resistant bacteria represent an urgent worldwide threat. NDM-1-producing strains are rendering the last line antibiotics less effective. Six bismuth complexes of general formula BiLCl2, where L is a thiosemicarbazone bearing a quinoline moiety, have been synthesized and fully characterized, including their X-ray crystal structures. The synergistic relationship between the compounds and meropenem have been tested in a combination therapy in carbapenem-resistant Klebsiella pneumoniae (NTCT14331) carrying the NDM-1 gene. Quinoline-2-carboxaldehyde-N-4-phenyl-3-thiosemicarbazone bismuth dichloride and carbapenem showed synergism in a dose dependent manner with negligible antibacterial activity when used in a monotherapy and could restore antibiotic sensitivity in the strain producing NDM-1 enzyme. The minimum inhibitory concentration (MIC) of meropenem lowered down 128 folds up to 2 mu gmL(-1), a concentration lower to the sensitivity level. The IC50 of the compound against A549 human lung carcinoma cells and HuDe human epithelial tissue was 46.96 & PLUSMN; 16.66 mu M and 54.26 & PLUSMN; 9.89 mu M respectively. The cytotoxicity against human cells was higher than the effective concentration needed for the synergistic effect in bacterial cells, indicating that a structural optimization of the compounds is needed.

Automated summary

Resistant bacteria pose a global threat. Bismuth complexes and carbapenem show synergistic effects against carbapenem-resistant Klebsiella pneumoniae carrying the NDM-1 gene, reducing the minimum inhibitory concentration of meropenem.