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Background The rise of multidrug-resistant (MDR) bacteria is a real public health problem worldwide and is responsible for the increase in hospital infections. Donella welwitschii is a liana or shrub belonging to the family Sapotaceae and traditionally used to cure coughs. Objective This study was conducted with the objective to validate the medicinal properties of this plant, the aerial part was studied for its phytochemical composition using column and PTLC chromatography and exploring its antibacterial and antibiotic-modifying activity as well as those of its phytochemicals. Methods The structures of the compounds were elucidated from their physical and spectroscopic data in conjunction with literature. The antibacterial activity of the isolated metabolites was performed toward a panel of MDR Gram negative and Gram-positive bacteria. The broth micro-dilution method was used to determine antibacterial activities, efflux pump effect using the efflux pump inhibitor (EPI) (phenylalanine-arginine-ß-naphthylamide (PAβN)), as well as the modulating activity of antibiotics. Monitoring the acidification of the bacterial growth medium was used to study the effects of the samples on the bacterial proton-ATPase pumps and cellular ATP production. Results Eleven compounds were isolated including pentacyclic triterpenes, C-glucosyl benzophenones. With a MIC value < 10 μg/mL, diospyric acid (7) significantly inhibited the growth of Escherichia coli AG102, Enterobacter aerogenes ATCC13048, Klebsiella pneumoniae KP55, Providencia stuartii NEA16 and Staphylococcus aureus MRSA3. 28-hydroxy-β-amyrin (8) significantly impaired the growth of Enterobacter aerogenes EA27, Klebsiella pneumoniae ATCC11296 and Staphylococcus aureus MRSA6; and oleanolic acid (9) strongly impaired the growth of Escherichia coli AG 102, Enterobacter aerogenes EA27 and Providencia stuartii PS2636. Diospyric acid (7) and 28-hydroxy-β-amyrin (8) induced perturbation of H+-ATPase pump and inhibition of the cellular ATP production. Moreover, at MIC/2 and MIC/4, compounds 7, 8, and 9 strongly improved the antibacterial activity of norfloxacin, ciprofloxacin and doxycycline with antibiotic-modulating factors ranging between 2 and 64. Conclusion The overall results of the current work demonstrate that diospyric acid (7), 28-hydroxy-β-amyrin (8) and oleanolic acid (9) are the major bioactive constituents of Donella welwitschia towards Gram-negative bacteria expressing MDR phenotypes.

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