Abstract
The emergence of antibiotic resistance has made many of the first-line antibiotics ineffective. The search for novel antimicrobial entities is, therefore, being vigorously pursued. We report here a thousand-fold resistance reversal when a monoterpene benzoic ester, tschimganin (1), in combinations of antibiotics, was screened against various strains of multi-drug resistant (MDR) Staphylococcus aureus. Compound 1 was obtained from Ferula ovina (Bioss.) Bioss, which is an Iranian medicinal plant used as a traditional flavoring agent. It is also used in medicines as antispasmodic, anticholinergic and smooth muscle relaxant. The effetcs of the tschimganin (1) on the depolarization of the bacterial cell membrane was evaluated by flow cytometery. Lucigenin chemiluminescence assay was employed to evaluate the generation of reactive oxygen species (ROS) in MDR bacterial cells when exposed to compound 1. The reversal of multi-drug resistance by tschimganin (1), in combination with selected antibiotics, was evaluated through fractional inhibitory concentration index (FICI) assay. The ultra-structural changes in bacterial cells after the treatment of tschimganin (1) were studied by using scanning and transmission electron microscopy. The anti-bacterial activity of tschimganin (1) in the presence of blood (ex vivo) was also studied. In brief, compound 1 facilitates the anionic probe to enter into the depolarized bacterial cell membrane and binds with the lipid rich cellular components, indicating the lethal effect of 1. Most importantly, it reverses the drug resistance and augments the sensitivity of already failed antibiotics by lowering their minimum inhibitory concentrations (MICs). The monoterpene tschimganin (1) was thus identified as a new resistance reversal agent against MDR Staphylococcus aureus.
Keywords: Ferula ovina, Monoterpene, Tschimganin, Multi-drug Resistant Staphylocoocus aureus, Bacterial cell membrane depolarization, Fraction inhibitory concentration (FIC).
Graphical Abstract
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