Drug Metabolism Letters

Zhiyang Zhao
Amgen
Cambridge, MA
USA

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Synergistic Antimicrobial Activity of Combinations of Sanguinarine and EDTA with Vancomycin Against Multidrug Resistant Bacteria

Author(s): Razan Hamoud, Jurgen Reichling, Michael Wink.

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.

Keywords: Drug interactions, EDTA, multidrug resistance, sanguinarine, synergy, vancomycin.

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Article Details

VOLUME: 8
ISSUE: 2
Year: 2014
Page: [119 - 128]
Pages: 10
DOI: 10.2174/187231280802150212100742
Price: $58