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Link to original content: http://pubmed.ncbi.nlm.nih.gov/10677479
Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor - PubMed Skip to main page content
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. 2000 Feb 15;97(4):1433-7.
doi: 10.1073/pnas.030540597.

Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor

F R Stermitz  1 , P Lorenz, J N Tawara, L A Zenewicz, K Lewis
Affiliations

Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5'-methoxyhydnocarpin, a multidrug pump inhibitor

F R Stermitz et al. Proc Natl Acad Sci U S A. .

Abstract

Multidrug resistance pumps (MDRs) protect microbial cells from both synthetic and natural antimicrobials. Amphipathic cations are preferred substrates of MDRs. Berberine alkaloids, which are cationic antimicrobials produced by a variety of plants, are readily extruded by MDRs. Several Berberis medicinal plants producing berberine were found also to synthesize an inhibitor of the NorA MDR pump of a human pathogen Staphylococcus aureus. The inhibitor was identified as 5'-methoxyhydnocarpin (5'-MHC), previously reported as a minor component of chaulmoogra oil, a traditional therapy for leprosy. 5'-MHC is an amphipathic weak acid and is distinctly different from the cationic substrates of NorA. 5'-MHC had no antimicrobial activity alone but strongly potentiated the action of berberine and other NorA substrates against S. aureus. MDR-dependent efflux of ethidium bromide and berberine from S. aureus cells was completely inhibited by 5'-MHC. The level of accumulation of berberine in the cells was increased strongly in the presence of 5'-MHC, indicating that this plant compound effectively disabled the bacterial resistance mechanism against the berberine antimicrobial.

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Figures

Figure 1
Figure 1
Structural formulas of NorA substrates and inhibitors. Substrates that are weak bases are shown in their cationic form. 5′-MHC is the MDR inhibitor identified in this study.
Figure 2
Figure 2
Medicinal plants producing berberine and the MDR inhibitor 5′-MHC. (Top) B. fremontii. (Middle) B. repens. (Bottom) B. aquifolia.
Figure 3
Figure 3
Synergistic action of berberine and 5′-MHC. (a) Growth inhibition of S. aureus. Berberine was present at a concentration of 30 μg/ml when combined with 5′-MHC. Measurements were performed in triplicate, and the average values are shown. (b) Inhibition of NorA transport activity by 5′-MHC. S. aureus cells were loaded with EtdBr and washed, and efflux was measured in the presence of 100 mM formate, a respiratory substrate. 5′-MHC was added at a final concentration of 10 μg/ml. (c) Cells were loaded with berberine and efflux was measured in the presence of formate. (d) Uptake of berberine added at time 0 by cells in the presence of formate. A small increase of fluorescence produced by 5′-MHC alone was subtracted from the plot.
Figure 4
Figure 4
A model of synergistic action of berberine and an MDR inhibitor that are both produced by B. fremontii. Berberine accumulates in the cell driven by the membrane potential. The NorA pump extrudes berberine. The MDR inhibitor 5′-MHC blocks the NorA pump, potentiating the antibiotic action of berberine.
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