Synergistic antibacterial activity of the combination of the alkaloid sanguinarine with EDTA and the antibiotic streptomycin against multidrug resistant bacteria

Objectives Drug combinations consisting of the DNA intercalating benzophenanthridine alkaloid sanguinarine, the chelator EDTA with the antibiotic streptomycin were tested against several Gram-positive and Gram-negative bacteria, including multi-resistant clinical isolates. Methods Microdilution, checkerboard and time kill curve methods were used to investigate the antibacterial activity of the individual drugs and the potential synergistic activity of combinations. Key findings Sanguinarine demonstrated a strong activity against Gram-positive and Gram-negative bacteria (minimum inhibitory concentrations, MIC = 0.5–128 μg/ml), while streptomycin was active against Gram-negative strains (MIC = 2–128 μg/ml). EDTA showed only bacteriostatic activity. Indifference to synergistic activity was seen in the two-drug combinations sanguinarine + EDTA and sanguinarine + streptomycin (fractional inhibitory concentration index = 0.1–1.5), while the three-drug combination of sanguinarine + EDTA + streptomycin showed synergistic activity against almost all the strains (except methicillin-resistant Staphylococcus aureus), as well as a strong reduction in the effective doses (dose reduction index = 2–16 times) of sanguinarine, EDTA and streptomycin. In time kill studies, a substantial synergistic interaction of the three-drug combination was detected against Escherichia coli and Klebsiella pneumoniae. Conclusions The combination of drugs, which interfere with different molecular targets, can be an important strategy to combat multidrug resistant bacteria.