title: Synergistic antimicrobial activity of combinations of sanguinarine and EDTA with vancomycin against multidrug resistant bacteria.
abstract: A combination of antimicrobial drugs has a potential to overcome multidrug resistant pathogens. In our study we tested the combination of an antimicrobial DNA-intercalating alkaloid (sanguinarine), a chelator (EDTA) with a standard antibiotic (vancomycin), i.e. drugs, which differ in their mode of action. The antibacterial activities of individual substances and of two-drug and three-drug combinations were evaluated for 34 strains of Gram-positive and Gramnegative bacteria (among them 23 clinical isolates) which are not sensitive for vancomycin. MIC and MBC values were determined for each drug individually. Sanguinarine demonstrated a strong activity against all the strains; its activity was comparable to that of antibiotics (MIC = 0.5 - 128 µg/ml). Time kill pharmacokinetics were studied for different concentrations of sanguinarine. A sanguinarine concentration of 16 x MIC was bactericidal against both Gram-positive and Gram-negative strains within 4 to 6 h of incubation. EDTA has only bacteriostatic activity against both Gram-positive and Gram-negative bacteria. As expected, vancomycin is active against Gram-positive bacteria (MIC = 0.125 - 16 µg/ml) but much weaker against Gram-negative bacteria (MIC = 4 - 128 µg/ml). Using the checkerboard design, two- and threedrug combinations were evaluated. Additive and synergistic effects were recorded for all sanguinarine + EDTA and sanguinarine + EDTA + vancomycin combinations against Gram-negative bacteria. Time kill assays indicated that only the combination of 1 x MIC sanguinarine + 1 x MIC EDTA + 1 x MIC vancomycin resulted in a synergistic interaction against MRSA. In the combination assays Gram-negative bacteria became sensitive for vancomycin. More experiments are needed to demonstrate that such a combination strategy also works under in vivo conditions and is clinically relevant.
authors.forename: Razan
authors.initials: R
authors.lastname: Hamoud
authors.forename: Jurgen
authors.initials: J
authors.lastname: Reichling
authors.affiliation: Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, INF 364, Heidelberg, Germany. wink@uni-hd.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Wink
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D053119:Benzophenanthridines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004492:Edetic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D007546:Isoquinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D014640:Vancomycin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D053119:Benzophenanthridines; D007546:Isoquinolines; D014640:Vancomycin; D004492:Edetic Acid; C005705:sanguinarine