Zanthoxylum capense constituents and derivatives: Effects on the activity of antibiotics against Staphylococcus aureus strains

Bacterial resistance represents a serious threat to global public health, preventing the treatment worldwide of an increasing range of infections caused by common bacteria. To find new non-toxic antibacterial drugs with new mechanisms of action is urgently needed. The search for antibiotic modulators and efflux pump inhibitors is considered a valuable approach for fighting bacterial drug-resistance. Zanthoxylum capense Thunb. (Rutaceae) is a medicinal plant traditionally used in African countries to treat colds, flu and tuberculosis. Previously, bioassay-guided fractionation of the methanol extract of the roots of Z. capense led to the isolation of several compounds, mainly benzophenanthridine alkaloids. Some of them exhibited significant antibacterial activity, namely against Mycobacterium tuberculosis [1 – 2]. Further phytochemical study of the methanol extract of the same plant led to the isolation of six compounds including lignans, benzophenanthridine alkaloids and phenyl-propanoids. In order to obtain new derivatives, the compounds isolated in larger amounts were esterified using different acyl chlorides, yielding six new acylated derivatives. The chemical structures were assigned based on spectroscopic methods namely 1D and 2D-NMR (COSY, HMBC, HMQC, NOESY) experiments. In order to identify new antibiotic modulators, the compounds were evaluated for their antibacterial activities and modulatory effects on the MIC of antibiotics against reference and clinical MRSA Staphylococcus aureus strains. Furthermore, the compounds were also assessed for their potential as efflux pump inhibitors by using a fluorometric assay that measures the accumulation of the universal efflux pump substrate ethidium bromide. Some compounds showed significant antibiotic modulatory and efflux-inhibitory effects against S. aureus strains and may be valuable new leads against bacterial drug-resistance.