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-N4-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 μgmL−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 ± 16.66 μM and 54.26 ± 9.89 μM 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.