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Zanthoxylum capense enhances antibiotic activity.

Cabral V, Luo X, Junqueira E, Costa SS, Mulhovo S, Duarte A, Couto I, Viveiros M, Ferreira MJU. 2015. Enhancing activity of antibiotics against Staphylococcus aureus: Zanthoxylum capense constituents and derivatives. Phytomedicine 22:469-476.

Increasing antibiotic resistance drives urgency for research into new therapies or redesigned therapeutic strategies to maintain effectiveness against bacterial infections. Numerous resistance mechanisms have been identified including antibiotic inactivation, target-based mutation compromising drug binding, reduced permeability and efflux mechanisms that pump the drugs out. This latter mechanism in particular can convey resistance to both specific classes of antibiotics, but also to different unrelated antimicrobial agents, thus conferring a multi-drug resistance (MDR) phenotype to bacteria. Strategies to overcome MDR resistance mechanisms include combination therapies of two or more antibiotics, or combining an antibiotic with a bacterial resistance-modifying agent, such as efflux pump inhibitors, to increase the activity of the antibiotic.

Zanthoxylum capense, of the Rutaceae family, has long been used as a traditional medicine in Africa to treat a variety of conditions including colds, flu and tuberculosis. Previous studies on Z. capense have isolated compounds demonstrating antibacterial activity. In the present study, six compounds isolated from the roots of Z. capense, and seven ester derivatives were evaluated for antibacterial activity against methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA), and for potential activity as antibiotic modulators and efflux pump inhibitors.

In a preliminary screening for antibacterial and antibiotic modulatory activity, a reference strain, S. aureus ATCC6538, was used for evaluation of the compounds. None of the Z. capense compounds demonstrated any antibacterial activity at the concentration ranges tested (ranging from 0.8-100 [micro]g/ml). A combination assay between the 13 compounds and the antibiotics erythromycin, tetracycline and oxacillin, and ethidium bromide (EtBr) was performed to search for antibiotic modulatory activities. The best modulation effect was exhibited by the benzophenanthridine alkaloid oxychelerythrine, which reduced the MICs against S. aureus for oxacillin four-fold, and MICs of erythromycin, tetracycline and EtBr two-fold. Two other benzophenanthridine alkaloid compounds, oxynitidine and arnottianamide demonstrated some modulatory effect in combination with tetracycline, but the remaining compounds demonstrated no effect.

To assess the potential activity of the 13 compounds as efflux pump inhibitors, a real-time EtBr accumulation assay in a S. aureus ATCC6538 model was employed; an increase in EtBr accumulation being indicative of potential efflux pump inhibitory activity. The Z. capense compounds, ailanthoidiol diacetate and ailanthoidiol di-2-ethylbutanoate, were most effective in increasing the EtBr accumulation, demonstrating a potential for efflux pump inhibition, and accordingly potential for use in combination with other antibiotics.

Following these findings, these two compounds were analysed in further assays against four additional S. aureus strains including reference strain ATCC25923, its derivative [ATCC25923.sub.EtBr] adapted to overexpress the norA efflux pump gene, and two clinical MRSA strains with increased efflux activity; S. aureus SM1, resistant to methicillin and ciprofloxacin, and S. aureus SM39, methicillin resistant with reduced susceptibility to biocides. Both Z. capense compounds demonstrated a modulation effect in combination with ciprofloxacin against all S. aureus strains, except for SM1, and in combination with EtBr. Despite these combination modulatory effects, only a weak efflux inhibitory activity was observed, with authors suggesting other mechanisms likely to contribute to their activity.

The results from this study suggest a potential role for Z. capense constituents in restoring antibiotic activity or increasing susceptibility of antibiotics against resistant strains. As the study revealed the modulatory effects of the Z. capense compounds were not due to efflux pump inhibition, further understanding of the modulatory mechanisms should be a focus of future research.
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Publication:Australian Journal of Herbal Medicine
Article Type:Abstract
Date:Sep 1, 2015
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