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. 2023 Aug 4;24(15):12432.
doi: 10.3390/ijms241512432.

Deciphering the Broad Antimicrobial Activity of Melaleuca alternifolia Tea Tree Oil by Combining Experimental and Computational Investigations

Federico Iacovelli  1 , Alice Romeo  1 , Patrizio Lattanzio  1 , Serena Ammendola  1 , Andrea Battistoni  1 , Simone La Frazia  1 , Giulia Vindigni  2 , Valeria Unida  2 , Silvia Biocca  2 , Roberta Gaziano  3 , Maurizio Divizia  4 , Mattia Falconi  1
Affiliations

Deciphering the Broad Antimicrobial Activity of Melaleuca alternifolia Tea Tree Oil by Combining Experimental and Computational Investigations

Federico Iacovelli et al. Int J Mol Sci. .

Abstract

Tea Tree Oil (TTO) is an essential oil obtained from the distillation of Melaleuca alternifolia leaves and branches. Due to its beneficial properties, TTO is widely used as an active ingredient in antimicrobial preparations for topical use or in cosmetic products and contains about 100 different compounds, with terpinen-4-ol, γ-terpinene and 1,8-cineole (or eucalyptol) being the molecules most responsible for its biological activities. In this work, the antimicrobial activity of whole TTO and these three major components was evaluated in vitro against fungi, bacteria and viruses. Molecular dynamics simulations were carried out on a bacterial membrane model and a Coxsackievirus B4 viral capsid, to propose an atomistic explanation of their mechanism of action. The obtained results indicate that the strong antimicrobial activity of TTO is attributable to the induction of an altered membrane functionality, mediated by the incorporation of its components within the lipid bilayer, and to a possible ability of the compounds to bind and alter the structural properties of the viral capsid.

Keywords: antifungal activity; antimicrobial activity; antiviral activity; eukaryotic cells viability; membrane partitioning; molecular docking; molecular dynamics; tea tree oil; viral capsid binders.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Effect of TTO, terpinen-4-ol, γ-terpinene and 1,8-cineole on (A) S. typhimurium and (B) S. aureus growth. Control samples were grown in LB medium without any supplementation (ctrl), while compounds were tested at different concentrations (v/v), as indicated in the legends. Each absorbance value (OD595) is the mean value of three replicates.
Figure 2
Figure 2
Cytotoxic effect of TTO and its components on BGM cells. Cell viability was assessed using MTS and SRB assays after 2 h treatment with TTO, terpinene-4-ol, γ-terpinene and 1,8-cineole at different concentrations, as indicated. The values are the mean ± S.E.M of three independent experiments, normalized to control.
Figure 3
Figure 3
Snapshot extracted from the bacterial membrane–TTO simulation. The peptidoglycan glycosyltransferase is represented as a blue cartoon, while the membrane hydrophobic tails are shown as grey lines and the lipid polar heads as red spheres. TTO compounds are shown as spheres with γ-terpinene in orange, 1,8-cineole in green and terpinen-4-ol in yellow.
Figure 4
Figure 4
Heatmaps representing the thickness maps of the systems simulated in the absence (A) and presence (B) of TTO compounds.
Figure 5
Figure 5
Projections of the motion identified along the first eigenvector over the 3D structure of the protein simulated in the absence (A) and presence (B) of the TTO compounds. The direction of motion is described by the color ranging from red to blue, while the amplitude of motion by the width of the ribbon.
Figure 6
Figure 6
(A) The structure of Coxsackievirus B4 in complex with capsid binder CP17 (red spheres). VP1, VP2 and VP3 are represented by violet, red and salmon spheres, while VP4 is not shown being below the plane formed by the other three structures. (B) Complex between terpinen-4-ol (red spheres) and the five interacting protomers.
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