Pharmacological activities of allylbenzene and allylanisole phenylpropanoids: Inhibition of antibiotic resistance targets and toxicity profile in a Drosophila melanogaster model

Abstract

Introduction: The rapid emergence of multidrug-resistant bacteria has demanded the discovery of new drugs capable of inhibiting bacterial resistance mechanisms, such as those mediated by efflux proteins and β-lactamases. Objective: Considering the evidence indicating that phenylpropanoids are effective substances against bacterial resistance, the present study aimed to evaluate the antibacterial activity of compounds allylbenzene and allylanisol against the Staphylococcus aureus strain SA-K4414, which carries genes encoding the β-lactamase and QacA/B proteins. Methods: The Minimum Inhibitory Concentrations (MICs) were determined by the broth microdilution method. The expression of β-lactamase was verified through the association of the inhibitor sulbactam with the antibiotic ampicillin, while its inhibition was analyzed through the reduction of the penicillin MIC in the presence of phenolic compounds. The efflux pump inhibition was analyzed by the reduction in the MIC of the pump substrate ethidium bromide. The toxicity against Drosophila melanogaster was assessed by evaluating mortality and negative geotaxis through the fumigation method. Results: The results demonstrated that the phenylpropanoids failed to show relevant direct antibacterial activity, with MIC values above 1024 µg/mL. The association of allylbenzene and allylanisole with penicillin potentiated its antibacterial effect, reducing the antibiotic MIC (512 µg/mL) to 128 µg/mL and 256 µg/mL, respectively. The compounds also reduced the MIC of EtBr, indicating a possible inhibitory effect against the β-lactamase enzyme and the QacA/B efflux protein. Regarding toxicity, allylbenzene (after 12 h) and allylanisole (after 3 h) presented EC50 of 19.21 μL/mL and 11.07 μL/mL, respectively. These compounds also caused damage to the locomotor system of flies, which was potentiated following increasing concentrations and exposure period. Conclusion: It is concluded that the compounds allylbenzene and allylanisole can inhibit the resistance mechanisms mediated by the β-lactamase enzyme and the efflux protein QacA/B. However, due to the significant toxicity observed, further research is required to assess the safety of these compounds.