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. 2023 Feb 9;12(2):360.
doi: 10.3390/antibiotics12020360.

Hydrocinnamic Acid and Perillyl Alcohol Potentiate the Action of Antibiotics against Escherichia coli

Mariana Sousa  1   2 , Ana Cristina Afonso  1   2   3   4 , Lília Soares Teixeira  1   2 , Anabela Borges  1   2 , Maria José Saavedra  3 , Lúcia Chaves Simões  4 , Manuel Simões  1   2
Affiliations

Hydrocinnamic Acid and Perillyl Alcohol Potentiate the Action of Antibiotics against Escherichia coli

Mariana Sousa et al. Antibiotics (Basel). .

Abstract

The treatment of bacterial infections has been troubled by the increased resistance to antibiotics, instigating the search for new antimicrobial therapies. Phytochemicals have demonstrated broad-spectrum and effective antibacterial effects as well as antibiotic resistance-modifying activity. In this study, perillyl alcohol and hydrocinnamic acid were characterized for their antimicrobial action against Escherichia coli. Furthermore, dual and triple combinations of these molecules with the antibiotics chloramphenicol and amoxicillin were investigated for the first time. Perillyl alcohol had a minimum inhibitory concentration (MIC) of 256 µg/mL and a minimum bactericidal concentration (MBC) of 512 µg/mL. Hydrocinnamic acid had a MIC of 2048 µg/mL and an MBC > 2048 µg/mL. Checkerboard and time-kill assays demonstrated synergism or additive effects for the dual combinations chloramphenicol/perillyl alcohol, chloramphenicol/hydrocinnamic acid, and amoxicillin/hydrocinnamic acid at low concentrations of both molecules. Combenefit analysis showed synergism for various concentrations of amoxicillin with each phytochemical. Combinations of chloramphenicol with perillyl alcohol and hydrocinnamic acid revealed synergism mainly at low concentrations of antibiotics (up to 2 μg/mL of chloramphenicol with perillyl alcohol; 0.5 μg/mL of chloramphenicol with hydrocinnamic acid). The results highlight the potential of combinatorial therapies for microbial growth control, where phytochemicals can play an important role as potentiators or resistance-modifying agents.

Keywords: antibiotic recalcitrance; combinatorial therapy; hydrocinnamic acid; perillyl alcohol; phytochemical-antibiotic interaction; plant-based natural product.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Matrix synergism plot (top) and synergism mapped to D-R (bottom) for the combination perillyl alcohol/hydrocinnamic acid. The number of stars indicates the level of statistical significance for each score: (*) for a p-value less than 0.05, (**) for a p-value less than 0.01, and (***) for a p-value less than 0.001. The data used are the mean ± standard deviation for three independent experiments.
Figure 2
Figure 2
Matrix synergism plot (left) and synergism mapped to D-R (right) for the combinations: (a) chloramphenicol/perillyl alcohol; (b) chloramphenicol/hydrocinnamic acid. The number of stars indicates the level of statistical significance for each score: (*) for a p-value less than 0.05, (**) for a p-value less than 0.01, and (***) for a p-value less than 0.001. The data used are the mean ± standard deviation for three independent experiments.
Figure 3
Figure 3
Matrix synergism plot (left) and synergism mapped to D-R (right) for the combinations: (a) amoxicillin/perillyl alcohol; (b) amoxicillin/hydrocinnamic acid; (c) amoxicillin/metronidazole. The number of stars indicates the level of statistical significance for each score: (*) for a p-value less than 0.05, (**) for a p-value less than 0.01, and (***) for a p-value less than 0.001. The data used are the mean ± standard deviation for three independent experiments.
Figure 3
Figure 3
Matrix synergism plot (left) and synergism mapped to D-R (right) for the combinations: (a) amoxicillin/perillyl alcohol; (b) amoxicillin/hydrocinnamic acid; (c) amoxicillin/metronidazole. The number of stars indicates the level of statistical significance for each score: (*) for a p-value less than 0.05, (**) for a p-value less than 0.01, and (***) for a p-value less than 0.001. The data used are the mean ± standard deviation for three independent experiments.
Figure 4
Figure 4
Time-kill curves for individual compounds: chloramphenicol (top left), amoxicillin (top right), perillyl alchool (bottom left), and hydrocinnamic acid (bottom right). Two negative controls are presented: E. coli and E. coli plus the solvent. Values are the mean ± standard deviation for at least two independent experiments.
Figure 5
Figure 5
Time-kill curves for dual combinations: chloramphenicol/perillyl alcohol (top left), chloramphenicol/hydrocinnamic acid (top right), amoxicillin/perillyl alcohol (middle left), amoxicillin/hydrocinnamic acid (middle right), amoxicillin/metronidazole (bottom left), and perillyl alcohol/hydrocinnamic acid (bottom right). Two negative controls are presented: E. coli and E. coli plus the solvent. Values are the mean ± standard deviation for at least two independent experiments.
Figure 6
Figure 6
Time-kill curves for triple combinations: chloramphenicol/perillyl alcohol/hydrocinnamic acid (top) and amoxicillin/perillyl alcohol/hydrocinnamic acid (bottom). Two negative controls are presented: E. coli and E. coli plus the solvent. Values are the mean ± standard deviation for at least two independent experiments.
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