In-Depth Study of <i>Thymus vulgaris</i> Essential Oil: Towards Understanding the Antibacterial Target Mechanism and Toxicological and Pharmacological Aspects

Akermi, Sarra; Smaoui, Slim; Fourati, Mariam; Elhadef, Khaoula; Chaari, Moufida; Chakchouk Mtibaa, Ahlem; Mellouli, Lotfi

doi:https://doi.org/10.1155/2022/3368883

BioMed Research International

On this page

Abstract Introduction Materials and Methods Results and Discussion Conclusion Data Availability Conflicts of Interest Acknowledgments References Copyright Related Articles

Special Issue

Beneficial and Harmful Effects of Aromatic Medicinal Plants

View this Special Issue

Research Article | Open Access

Volume 2022 | Article ID 3368883 | https://doi.org/10.1155/2022/3368883

In-Depth Study of Thymus vulgaris Essential Oil: Towards Understanding the Antibacterial Target Mechanism and Toxicological and Pharmacological Aspects

Sarra Akermi,¹Slim Smaoui,¹Mariam Fourati,¹Khaoula Elhadef,¹Moufida Chaari,¹Ahlem Chakchouk Mtibaa,¹and Lotfi Mellouli¹

Academic Editor: Riaz Ullah

Received31 May 2022

Accepted05 Jul 2022

Published21 Jul 2022

Abstract

Questions have been raised apropos the emerging problem of microbial resistance, which may pose a great hazard to the human health. Among biosafe compounds are essential oils which captured consumer draw due to their multifunctional properties compared to chemical medication drugs. Here, we examined the chemical profile and the mechanism(s) of action of the Thymus vulgaris essential oil (TVEO) against a Gram-negative bacterium Salmonella enterica Typhimurium ATTCC 10028 (S. enterica Typhimurium ATTCC 10028) and two Gram-positive bacteria Staphyloccocus aureus ATCC 6538 (S. aureus ATCC 6538) and Listeria monocytogenes ATCC 19117 (L. monocytogenes ATCC 19117). Findings showed that TVEO was principally composed of thymol, o-cymene, and γ-terpinene with 47.44, 16.55, and 7.80%, respectively. Molecular docking simulations stipulated that thymol and β-sesquiphellandrene (a minor compound at 1.37%) could target multiple bacterial pathways including topoisomerase II and DNA and RNA polymerases of the three tested bacteria. This result pointed plausible impairments of the pathogenic bacteria cell replication and transcription processes. Through computational approach, the VEGA quantitative structure–activity relationship (QSAR) model, we revealed that among twenty-six TVEO compounds, sixteen had no toxic effects and could be safe for human consumption as compared to the Food and Drug Administration (FDA) approved drugs (ciprofloxacin and rifamycin SV). Assessed by the SwissADME server, the pharmacokinetic profile of all identified TVEO compounds define their absorption, distribution, metabolism, and excretion (ADME) properties and were assessed. In order to predict their biological activity spectrum based on their chemical structure, all TVEO compounds were subjected to PASS (Prediction of Activity Spectra for Substances) online tool. Results indicated that the tested compounds could have multiple biological activities and various enzymatic targets. Findings of our study support that identified compounds of TVEO can be a safe and effective alternative to synthetic drugs and can easily combats hazardous multidrug-resistant bacteria.

1. Introduction

In recent years, antimicrobial-resistant (AMR) bacteria have been admitted as a public health risk that could cause an increase in the global burden of infectious disease [1–4]. For instance, each year, more than 670,000 infections and 700,000 deaths worldwide were provoked by AMR [5, 6]. Mutually controlled by host immune condition, microflora organization, and antimicrobial interventions, AMR evolution occurs with the multidrug resistance [7, 8]. While AMR could not be pragmatically eradicated, antimicrobials will endure to miss their potency, and, in the close future, more people may die from infections [9–11]. Therefore, it is crucial to explore original effective and broad-spectrum antibacterial agents to control bacteria, which can be antibiotic resistant, highly virulent, and high costs for the medication. Among the leading strategies for the exploration and detection of new targets in pathogens are the masterfully using bioinformatics tools. These tools can provide useful information for better comprehension of the interactions between targets and biomolecules and therefore help to anticipate new treatment targets for pathogenic microorganisms [12, 13].

Extracted from natural plants, essential oils (EOs) can be exploited as a practical alternative. More specifically, thyme (Thymus vulgaris L.), appertained to the family of Lamiaceae and the genus of Thymus, was consumed for centuries because of its medicinal properties and was generally recognized as safe (GRAS) by the FDA [14–17]. In addition, essential oil acquired from Thymus vulgaris L. had an extensive range of biological activities [17]. Thyme EO contains high levels of phenolic compounds, like thymol, carvacrol, p-cymene, and γ-terpinene [17, 18]. Interestingly, numerous studies reported that thymol, the major antibacterial component occurring in TEO, can destroy the bacterial cell membrane [19, 20]. Liu et al. revealed that thymol powerfully inhibit Pseudomans aeruginosa and directly change the cell structure [15]. P. aeruginosa cell membrane integrity is destroyed as evidenced by an increase in permeability of the inner/outer membranes. In other studies, Wang et al. and Lade et al. noted that thymol disrupts the Staphylococcus aureus membrane integrity to achieve the inner structure of the bacterial cell and joints to the minor groove of bacterial DNA, ensuring in a destabilization of the DNA secondary structure [21, 22].

In extension of our research to disclose the potential of natural therapeutic agents [13], this current investigation is aimed at elucidating the molecular docking interactions of all components of Thymus EO with bacterial DNA and RNA polymerases, as well as the topoisomerase II of S. aureus, S. enterica Typhimurium, and L. monocytogenes were profoundly reviewed in silico. As a part of our endeavor to increase the potential and exploration of these activities, a pharmacokinetics and computational toxicological studies were well discussed.

2. Materials and Methods

2.1. Plant Material, Essential Oil Extraction, and Gas Chromatography–Mass Spectrometry (GC–MS) Analysis

2.1.1. Plant Material Collection and EO Extraction

Thymus vulgaris L. plant was collected from the region of Sfax, Tunisia (N: 34.4426°, E: 10.4537°) which is characterized by a semiarid climate. Aerial parts were harvested during the flowering stage in April 2022 and were air-dried in obscurity at room temperature. The EO of dried samples of T. vulgaris (TVEO) aerial parts was hydrodistilled for 3 h using a Clevenger apparatus.

2.1.2. EO Analysis Using Gas Chromatography–Mass Spectrometry (GC–MS)

The analysis of TVEO was accomplished using a GC/MS HP model 6980 inert MSD, equipped with an Agilent Technologies capillary HP-5MS column (, 0.25 mm film thickness) coupled to a mass selective detector (MSD5973, ionization voltage 70 eV, all Agilent, Santa Clara, CA, USA). The carrier gas was helium and has been maintained at 1.2 mL/min flow rate. The oven temperature program was as follows: 1 min at 100°C ramped from 100 to 280°C at 5°C/min and 25 min at 280°C. The chromatograph was equipped with a split/split less injector used in the split less mode. Identification of TVEO components was achieved by matching their mass spectra with Wiley Registry of Mass Spectral Data 7th edition (Agilent Technologies) and National Institute of Standards and Technology 05 MS (NIST) library data.

2.2. Antibacterial Activity

2.2.1. Microorganisms and Growth Conditions

In order to evaluate TVEO antibacterial activity, two Gram-positive bacteria: S. aureus ATCC 6538 and L. monocytogenes ATCC 19117, and two Gram-negative bacteria: S. enterica Typhimurium ATCC 14028 and E. coli ATCC 8739, were selected. Bacterial cultures were deposited in 3 mL of Luria-Bertani (LB) agar medium composed of (g/L): peptone, 10; yeast extract, 5; NaCl, 5; and agar, 20 at pH 7.2; then, the bacterial strains were incubated at 37°C according to the method described by [23].

2.2.2. Agar Diffusion Method

Antimicrobial activity of TVEO was evaluated by agar-well diffusion assay according to a method proposed by Güven et al. [24]. Fifteen milliliters of the molten agar (45°C) were flowed into sterile Petri dishes ( 90 mm). Bacterial cell suspensions were prepared, and 100 μL was evenly deposited onto the surface of plates containing LB agar medium. Plates were aseptically dried, and then, 5 mm wells were punched into the agar with a sterile Pasteur pipette. TVEO was dissolved in DMSO, water (1/9; ) to a final concentration of 1 mg/mL and then filtered through 0.22 μm pore size black polycarbonate filters. 100 μL of this filtered solution was placed into each well, and the plates were incubated at 37°C. Gentamicin (10 μg/wells) was used as a positive control.

2.2.3. Minimal Inhibitory Concentration (MIC)

MIC is defined as the lowest concentration that could inhibit the visible growth of the tested microorganism. In this context, MIC of TVEO was tested against four pathogenic bacteria which are as follows: two Gram-positive bacteria: S. aureus ATCC 6538 and L. monocytogenes ATCC 19117, and two Gram-negative bacteria: S. enterica Typhimurium ATCC 14028 and E. coli ATCC 8739, using the microdilution method with serial dilution described by Chandrasekaran and Venkatesalu [25]. Then, bacterial suspension was added with a final inoculum concentration of 10⁶ CF/mL. The contents of the tubes were mixed by pipetting and were incubated for 24 h at 37°C. For the antibacterial activity determination (inhibition zones and CMIs), each experiment was carried out simultaneously in triplicate under same conditions. The obtained diameters of inhibition zones were measured in mm and the MIC values were reported in mg/mL.

2.3. Interaction Study between TVEO Compounds and Selected Bacterial Targets by Molecular Docking

Receptor targets Fasta sequences of S. aureus ATCC 700699, S. enterica Typhimurium ATCC 700720, and L. monocytogenes ATCC 19115 were obtained from UniProt database [26] and NCBI database [27]. Protein models were projected to SWISS-MODEL server [28] for molecular homology modeling approach [29]. Validation of the obtained models was performed by checking Ramachandran plots and the QMEAN values [30], using PROCHECK analysis tool integrated in Profunc server ([31]. SMILES (simplified molecular input line entry systems) strings of TVEO compounds were obtained from the PubChem database [32] and controls (rifamycin SV and ciprofloxacin). SMILES structures were downloaded from the DrugBank database [33], and all were converted into 3D structure using CORINA demo webserver [34] and then saved in pdb file format. Molecular docking was performed using the AutoDock Vina software (version 1.2.0) to calculate free energy of binding (kcal/mol) scores according to the methodology proposed by [35]. The docking position results were visualized using Discovery Studio version 16.1.0 (Dassault Systemes BIOVIA, 2016).

2.4. Toxicity Prediction of Compounds by VEGA HUB Software Using QSAR Method

All TVEO compounds and the two controls (rifamycin SV and ciprofloxacin) were subjected to 8 toxicity measurements in a view to assess carcinogenicity, mutagenicity, developmental/reproductive toxicity, endocrine disrupting ability, and genotoxicity. All tests were performed by VEGA software version 1.1.5 using the QSAR (quantitative structure–activity relationship) approach [36].

2.5. ADME Analysis

Pharmacokinetics, drug-likeness, and medicinal chemistry properties of TVEO compounds were predicted using SwissADME which is an open access software for ADME parameters evaluation and profiling [37].

2.6. In Silico Prediction of Possible Bioactivities

The PASS software was used to predict bioactivity of molecules based on the structural similarity to the large data base of known active substances in order to find new TVEO molecule targets [38, 39].

2.7. Statistical Analysis

All tests were assayed in triplicate and expressed as the of the measurements. The statistical program SPSS version 21.00 for Windows (SPSS Inc., Chicago, IL, USA) was used to analyze the data. Variance was analyzed by one-way ANOVA and Student’s -test was applied to compare each parameter at .

3. Results and Discussion

3.1. Chemical Composition Analysis of TVEO

GC-MS analysis of TVEO revealed the existence of 26 different components (Table 1). The main components were thymol, the most abundant compound (47.44%), followed by o-cymene (16.55%), γ-terpinene (7.80%), and linalool (4.41%). Moreover, it detected the presence of 4 compounds which their percentages (EO %) were more than 2%. These later are the α-zingibirene (3.40%), β-myrcene (2.36%), caryophyllene (2.09%), and borneol (2.02%).

Thymol, known also by the chemical name 2-isopropyl-5-methylphenol, is a natural phenol monoterpene [40] importantly detected in Lamiacaeae family [41] including many plant species such as Thymus vulgaris L. [42], Ocimum gratissimum L. [43], Origanum L. [44], and Trachyspermum ammi L. [45] and other species of the genus Satureja L. [46] and Monarda L. [47]. This volatile monoterpenoid is largely used by nutraceutical, pharmaceutical, and cosmeceutical industries due to its multiple potential therapeutic properties [48–58]. In addition, thymol was globally recognized-as-safe food additive according to US department of Food and Drug Administration (FDA) [59].

O-cymene, known as 1-isopropyl-2-methylbenzene, is an acyclic monoterpene which belongs to p-cymene isomers and has an orthosubstituted alkyle group [60]. Previous studies demonstrated that o-cimene has several therapeutic effects [61–66]. Several studies indicated the existence of a remarkable synergetic effect between ocimene and other terpenes such as α-pinene and myrcene which were noticed to produce more beneficial effects when combined [67, 68].

γ-Terpinene, renowned also as p-mentha-1,4-diene, is a naturally occurring monoterpene hydrocarbon [69] that has been isolated from many botanical sources including Origanum vulgare, Citrus limon L, Melaleuca alternifolia, and Eucalyptus obliqua [70, 71]. This monoterpene is largely employed in food, cosmetics, and pharmaceutical industries [72]. Previous research showed that γ-terpinene has potential biological activities such as antioxidant [73], anti-inflammatory [74], and antimicrobial activities [75, 76].

On the other hand, linalool, known as 3,7-dimethyl-1,6-octadien-3-ol [77], is a naturally occurring acyclic monoterpenoid and tertiary alcohol which is commonly found as a major active component in the essential oil of several aromatic plant species [78] principally in Lamiaceae and Lauraceae botanical families. It has been reported that this monoterpenol is broadly used in food industry as an aromatic and preservative agent, in cosmetic as a fragrance and antiseptic constituent [79–83].

It should be noted that TVEO composition may depend on many biotic and abiotic factors including seasonal variations of temperature and humidity [84], phenological stages and different vegetation cycles [85], geographic location [86], environmental stress [87], and extraction technique [88]. Aljabeili et al. reported that the TVEO collected from KSA showed a significant composition variation and the major compounds were thymol (41.04%), 1,8-cineole (14.26%), γ-terpinene (12.06%), and p-cymene (10.50%) [89]. Another study revealed that Turkish TVEO has different components amounts such as thymol (49%), β-cymene (19.99%), carvacrol (7.63%), and trans-caryophyllene (6.79%) [90]. In addition, Moghaddam et al. reported that Iranian TVEO contains thymol (36.81%), ρ-cymene (30.90%), and carvacrol (3.16%) [91].

3.2. Antibacterial Activity

As represented in Table 2, TVEO displayed an interesting antibacterial activity against the four tested bacterial strains with inhibition zones ranging from of 21 to 23 mm against Gram-negative and Gram-positive bacteria, respectively. In addition, it is important to note that monoterpenes exhibit a broad-spectrum antibacterial activity against pathogenic bacteria [92, 93]. This fact could be explained by the presence of a lipophilic character which provides to monoterpenes the ability to adhere to bacterial cell membrane lipids and to deploy their antibacterial action [94]. In our study, the obtained MIC values mentioned in Table 2, indicated that TVEO was more potent () against Gram-positive bacteria ( mg/mL) than Gram-negative bacteria ( mg/mL). These findings were in agreement with previous studies which reported that Gram-positive bacteria are susceptible to be more sensitive to plant EOs than Gram-negative bacteria due to the existence of lipopolysaccharides which acts as a hydrophobic barrier [95, 96].

3.3. Interactions between TVEO Molecules and Bacterial Topoisomerase II and DNA and RNA Polymerases

Computational modeling is a 3R-based approach and an attractive alternative to experiments in a view to understand bioactive compounds mechanism of action and their antibacterial inhibitory process [97]. Molecular docking was performed to predict different TVEO components that could bind specifically to select bacterial receptors active sites responsible for DNA replication and transcription processes. In this respect, we investigated TVEO antibacterial inhibitory effect on topoisomerase II (DNA gyrase) and DNA and RNA polymerases of three pathogenic bacteria S. aureus ATCC 700699, S. enterica Typhimurium ATCC 700720, and L. monocytogenes ATCC 19115. Molecular homology results indicated that selected templates can be used for molecular modeling (Table 3); their identities (%) are higher than 30% [98], and Ramachandran plot values of favored regions and allowed regions were over 90% [99].

Moreover, it is necessary to remind that DNA and RNA polymerases are crucial enzymes involved in the DNA replication, transcription, and translation as well as nucleic acid formation in bacterial cells [100]. On the other hand, topoisomerase II (DNA gyrase) is also implicated in DNA replication and transcription processes and has an imperative role characterized by its ability to catalyze the unwinding of supercoiled DNA strands [101]. These imperative enzymes constitute attractive and validated targets for antibacterial agents [102]. Molecular docking simulation results are elucidated by (Table 4). These later displayed that TVEO major compound thymol (47.44%) showed a good inhibitory effect on topoisomerase II, RNA polymerase, and DNA polymerase of the selected pathogenic bacteria.

A previous study conducted by Liu et al. reported that thymol has a potential antibacterial activity against P. aeruginosa [15]. This monoterpenoid can affect bacterial DNA normal function. It could block gene expression processes including replication, transcription, and expression by intercalation with bacterial DNA leading to bacterial death. The same study indicated that thymol could destroy bacterial membrane integrity by affecting its permeability and it could also hinder biofilm formation. Another research paper displayed that thymol could bind to bacterial DNA, modulate its structure, and prohibit its biological function [103]. Furthermore, dos Santos Barbosa et al. showed that the antibacterial inhibitory activity of Origanum vulgare EO was effective against Salmonella Enteritidis due to the presence of thymol which caused interference in protein regulation as well as DNA synthesis [104]. On the other hand, the minor compound β-sesquiphellandrene (1.34%) showed the lowest free energy of binding (Kcal/mol) and the highest inhibitory potential on topoisomerase II and DNA and RNA polymerases of the selected pathogenic bacteria (Table 4). A previous study reported that β-sesquiphellandrene was responsible for the high antibacterial and antioxidant activities of some pomelo varieties’ EOs [105]. Another study indicated that the presence of β-sesquiphellandrene presented in ginger (Zingiber officinale) essential oil could make this later as a potential antimicrobial agent by inhibiting mycobacterial acyl carrier protein reductase enzyme and Enoyl acyl carrier protein reductase activities [106].

A recent study showed that Cupressus sempervirens EO had a great inhibitory effect on DNA gyrase and DNA and RNA polymerases of S. aureus and S. enterica owing to the presence of α-pinene, δ-3 carene, and borneol [13]. Moreover, a previous study conducted by [107] evaluated the inhibitory effect of Litsea cubeba EO on topoisomerase and DNA and RNA polymerases of E.coli. Another study revealed that the germacrene B, a minor compound in Siparuna guianensis EO, had an effective inhibitory activity against bacterial DNA and RNA polymerases of multiple pathogenic bacteria including E.coli, P. aeruginosa, S. aureus, and S. pyogenes [108]. Therefore, these findings confirmed that TVEO has a powerful inhibitory effect on pathogenic bacteria based on the inhibition of DNA replication and transcription processes. Consequently, we project in subsequent work to perform further in vitro assays based on the evaluation of protein-molecule binding assays.

Interaction profiles details of thymol and β-sesquiphellandrene with the active sites of the selected targets of S. aureus ATCC 700699, S. enterica Typhimurium ATCC 700720, and L. monocytogenes ATCC 19115 are summarized in Table 5.

Interaction profile results of thymol and β-sesquiphellandrene with topoisomerase II and DNA and RNA polymerases of S. aureus are presented by Figures 1 and 2. Thymol made a complex with DNA polymerase receptor via alkyl interaction and conventional hydrogen bond with LYS228 and van der Waals interactions with ASN84, LYS88, LEU87, GLU469, TYR91, LEU227, and ILE492 (Figure 1(a)). Additionally, RNA polymerase complexed with thymol had alkyl and Pi-alkyl interaction with VAL536 and LYS35; van der Waals interactions with GLU413, SER410, GLY412, SER36, and GLU538; and Pi-sigma interaction with TRP39 (Figure 1(b)). Likewise, it interacted with topoisomerase II via alkyl interaction with ALA614; van der Waals interactions with HIS46, ARG198, TRP49, ARG42, THR194, GLN197, THR617, and LEU608; and two conventional hydrogen bonds with ASP610 and GLU609 (Figure 1(c)).

(a)

(b)

(c)

(a)

(b)

(c)

β-Sesquiphellandrene complexed with DNA polymerase showed Pi-alkyl interaction with LEU641 and van der Waals interactions with ILE938, LYS901, PHE900, ASP936, GLU939, ILE899, SER903, LEU902, and GLN975 (Figure 2(a)). When complexed with RNA polymerase, it made Pi-alkyl interaction with VAL270, LYS35, and VAL536; van der Waals interactions with SER36, SER410, GLY412, ARG407, GLN416, GLN413, GLU538, and ILE32; and Pi-sigma interaction with TRP39 (Figure 2(b)). Concerning topoisomerase II, β-sesquiphellandrene displayed alkyl and Pi-alkyl interactions with VAL606, PHE618, ILE532, ALA614, LEU521, and LEU608 and van der Waals interactions with LYS607, ARG198, GLU609, GLU613, ASP610, and TYR525 (Figure 2(c)).

On the other hand, interaction profiles between thymol and β-sesquiphellandrene with topoisomerase II and DNA and RNA polymerases of S. enterica Typhimurium are outlined in Figures 3 and 4. DNA polymerase complexed with thymol showed alkyl and Pi-alkyl interactions with ARG18 and LYS17 and van der Waals interactions with ASP1188, THR657, SER656, PRO19, ASN622, ASN620, SER621, LEU623, and ALA 619 (Figure 3(a)). Thymol complex with RNA polymerase indicated the presence of alkyl interaction with MET768 and van der Waals interactions with ASP785, GLN767, ASN766, GLY786, PRO787, SER788, PRO691, THR692, ALA695, THR789, and LEU693 (Figure 3(b)). This monoterpene also made interactions with topoisomerase II via alkyl interactions with VAL727, ILE557, and ALA560; van der Waals interactions with LEU561, VAL584, LEU723, GLN591, and ASP553; and one conventional hydrogen bond with ASN588 (Figure 3(c)).

(a)

(b)

(c)

(a)

(b)

(c)

The complex of β-sesquiphellandrene and the DNA polymerase of S. enterica Typhimurium revealed the existence of alkyl and Pi-akyl interactions with LEU75, ALA94, LEU129, LEU32, PHE35, and ILE39 and van der Waals interactions with GLN41, GLN36, GLY76, and MET130 (Figure 4(a)). This sesquiterpene complexed with RNA polymerase showed alkyl and Pi-alkyl interactions with MET130, LEU32, LEU129, PHE35, ALA94, and LEU75 and van der Waals interactions with ILE39, GLN36, and ASP32 (Figure 4(b)). In addition, it made interactions with topoisomerase II via alkyl and Pi alkyl interactions with VAL467, PHE513, PHE777, ARG516, and LEU462 and van der Waals interactions with MET461, LEU509, and THR512 (Figure 4(c)).

DNA polymerase receptor of L. monocytogenes complexed with thymol displayed the existence of alkyl and Pi-alkyl interactions with MET389, LEU345, LEU394, ILE392, and PHE367 and van der Waals interactions with GLU359, THR357, LYS358, ILE343, THR360, and SER364 (Figure 5(a)). It also showed when complexed with RNA polymerase alkyl interactions with LYS283 and LYS284 and van der Waals interactions with VAL150, GLY149, TYR151, ASN410, ASP403, ASP571, and ASN289 (Figure 5(b)). Further, thymol made interactions with topoisomerase II via alkyl interaction with PHE97; van der Waals interactions with GLN95, SER98, GLN267, TYR266, THR220, VAL268, ASN269, GLY115, and SER112; and one conventional hydrogen bond with VAL113 (Figure 5(c)).

(a)

(b)

(c)

Finally, β-sesquiphellandrene complex with DNA polymerase of L. monocytogenes indicated the existence of Alkyl interactions with MET386, ALA382, ILE399, and LEU488 and van der Waals interactions with SER397, PHE492, PRO489, GLU484, THR400, and THR491 (Figure 6(a)). It showed also with RNA polymerase alkyl interactions with LYS280, LYS284, and TYR151 and van der Waals interactions with VAL150, GLY149, ASP403, ASN410, ASP571, ASP404, ASP401, ASN289, and LYS283 (Figure 6(b)). In addition, β-sesquiphellandrene made a complex with topoisomerase II via alkyl and Pi-alkyl interactions with VAL113, ILE264, and PHE97 and van der Waals interactions with GLY115, SER112, GLN95, ARG92, GLY111, PHE88, SER98, ASN269, VAL268, THR220, PRO265, and TYR266 (Figure 6(c)).

(a)

(b)

(c)

3.4. In Silico TVEO Compound Toxicity Evaluation by VEGA QSAR Model

Toxicity evaluation of different TVEO compounds and the two selected FDA-approved antibiotics, used as controls (rifamycin SV and ciprofloxacin), was performed by the help of QSAR (quantitative structure–activity relationship) approach and using VEGA HUB software. We chose to assess compounds toxicity based on 8 different toxicity measurements. Results are represented by (Table 6) and revealed that FDA-approved drugs could be toxic in several assays. In this context, rifamycin SV and ciprofloxacin are found to be mutagenic in the mutagenicity test/model (Ames test) and predicted to engender developmental/reproductive toxicity. These two antibiotics were also predicted to be genotoxic according to the in vitro micronucleus activity model. However, many TVEO compounds such as α-pinene, α-thujene, camphene, β-pinene, 3-carene, D-limonene, γ-terpinene, terpinolene, linalool, borneol, 4-terpineol, α-terpineol, thymol, caryophyllene, α-bisabolene, and β-sesquiphellandrene showed nontoxic effects. Computational toxicity results confirmed that TVEO molecules could be used as a safe antimicrobial agents and economically low-cost alternative as compared to synthetic antibiotics. It is important to mention that research related to toxicological profiles of different essential oil compounds are poorly studied due to experiments complexity, expensive cost, and difficulty to detect toxicity variation because of the chemical function and factor variability [109]. However, previous studies indicated that toxicity is a dose-/concentration-dependent manner and thymol could have a certain limit of toxicity ranging from 36 mg/mL to 49 mg/mL with less risks of accumulation in body tissues and suggested to replace synthetic drugs, which has more side effect [110]. In addition, Schönknecht et al. confirmed the safety and the effectiveness of the drug containing the extracts of thyme with the addition of thymol (Bronchosol®) in cough treatment instead of using the synthetic drug ambroxol [111]. Concerning β-sesquiphellandrene, it was reported that this sesquiterpenoid could have a great anticancer activity and can be safe to use as compared to synthetic chemotherapeutic agents velcade, thalidomide, and capecitabine [112]. Nevertheless, more toxicological in vitro/in vivo data are needed to validate the safety of these phytochemicals. Thus, computational toxicity assessment could be the best alternative that would give robust data, avoid unnecessary waste of reagents, and minimize cruelty and sacrifices of lab animal testing.

3.5. TVEO Component ADME Analysis

In the present study, SwissADME server was used to determine some pharmacokinetics parameters included in absorption, distribution, metabolism, and excretion (ADME), drug-likeness, and medicinal chemistry characteristics for all TVEO compounds as represented in (Table 7). Results revealed that all TVEO components possess slow passive gastrointestinal absorption (GI) except linalool, camphor, borneol, 4-terpineol, α-terpineol, thymol methyl ether, and thymol which were predicted to have high GI permeability. Additionally, only sesquiterpenes including caryophyllene, α-humulene, α-amorphene, α-curcumene, α-zingibirene, α-bisabolene, and β-sesquiphellandrene were found not to be blood-brain barrier (BBB) permanent due to their heavy molecular weight. However, rest of compounds could easily cross the blood-brain barrier for that reason it could be suggested as potent central nervous system antioxidants and effective drug candidates in the treatment of neurodegenerative diseases like Alzheimer’s and Parkinson’s [113]. On the other part, none of the tested compounds was predicted to be P-gp transporter substrate. Concerning Cytochrome p450 (CYP) isoenzymes which are involved in 50-90% of therapeutic molecules biotransformation processes in a view to reduce metabolites accumulation in blood/tissues and drug-drug interaction risks [114], thymol methyl ether and thymol were predicted to be CYP1A2 inhibitors. Many TVEO molecules were predicted to inhibit CYP2C9 and CYP2D6 inhibitors. However, none of the compounds showed an inhibitory effect towards the CYP3A4. Moreover, skin permeation coefficient () indicated that all compounds were impermeable through the skin barrier. Interestingly, TVEO drug-likeness score was acceptable with good bioavailability score (>10%) and the absence of violations related to known rules such as Lipinski’s rule of five that predicts drug permeability and absorption based on H-bond donors, H-bond acceptors, molecular weight (), and a calculated ) [115], as well as Veber. Both rules are a mainstay of decision-making in drug design and development and in the present study; both were validated. Furthermore, medicinal chemistry parameters revealed that none of the selected molecules returns any pan-assay interference compounds (PAINS) alert. The synthetic accessibility values of TVEO compounds indicated that these later could be synthesized for pharmaceutical uses.

3.6. Prediction of Possible Activity Spectra of TVEO Components

All TVEO compounds were subjected to PASS (Prediction of Activity Spectra for Substances) online tool intending to predict their biological activity spectrum based on their chemical structure. Results indicated that the tested compounds could have multiple biological activities and various enzymatic targets (Table 8). We have selected the top three activities which showed a . Pa and Pi values indicated the probability of the selected molecule to be active/ inactive towards the targeted receptor. Mojumdar et al. reported that the probability of experimental pharmacological action is high when ; however, the chance of finding the activity experimentally is less when [116]. Interestingly, TVEO major compounds such as thymol which were predicted, in earlier section by molecular docking, to have a potent antibacterial activity on pathogenic bacteria by inhibiting DNA replication and transcription processes, displayed the existence of other biological activities including the ability to inhibit bacterial membrane permeability () and it was anticipated to enhance AP0A1 expression () involved in the cellular synthesis of beneficial HDL [117]. In addition, O-cymene was predicted to be mitochondria ubiquinol-cytochrome-c reductase inhibitor () (antifungal activity), mucomembranous protector (), and a fibrinolytic agent () which could stimulate the dissolution of blood clots. Concerning γ-terpinene, it was predicted to treat skin eczema () and phobic disorders () owing to its ability to cross the blood-brain barrier (BBB). Finally, PASS prediction revealed that the minor compound β-sesquiphellandrene has other possible biological activities including antineoplastic effect () and antipsoriatic () and could be also used as immunosuppressant agent during organ transplant () instead of using synthetic compounds such as cyclosporin A which was demonstrated to cause severe cholestatic liver disease [118]. These findings could provide more insights towards further in vivo and in vitro assays to validate the computational predictions.

4. Conclusion

The dramatical increase of antibiotic resistance urged scientists to diverge towards the use of aromatic medicinal plants essential oils to tackle the spread of superbugs. In that regard, the present study is aimed at investigating the TVEO chemical composition and antibacterial mechanism of action against S. aureus ATCC 6538, S. enterica Typhimurium ATCC 14028, and L. monocytogenes ATCC 19117. In addition, chemocomputational toxicological profile and pharmacological proprieties were developed. Interestingly, molecular docking simulations revealed that TVEO compounds such as thymol and β-sesquiphellandrene had an effective antibacterial activity against the tested bacteria by inhibiting topoisomerase II and DNA and RNA polymerase functions leading to vigorous impairment of bacterial DNA replication and transcription processes. Additionally, through VEGA QSAR, we demonstrated that TVEO could be a safe resource for potential antibacterial agents. Moreover, ADME analysis showed that both compounds fulfill the Lipinski’s rule of five and could be used as potential candidate to overcome antibiotic resistance. Likewise, the in silico PASS prediction studies disclosed the presence of other useful bioactivities and possible enzymatic targets of TVEO which would be applied in the future to reduce the impact of several lethal diseases.

Data Availability

All the relevant data have been provided in the manuscript. The authors will provide additional details if required.

Conflicts of Interest

The authors declare no conflicts of interest.

Acknowledgments

This research was funded by the Tunisian Ministry of Higher Education and Scientific Research program contract (2019-2022) of the Laboratory of Microbial Biotechnology and Enzymes Engineering (LR15CBS06) of the Center of Biotechnology of Sfax–University of Sfax-Tunisia.

References

C. J. Murray, K. S. Ikuta, F. Sharara et al., “Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis,” The Lancet, vol. 399, no. 10325, pp. 629–655, 2022.
View at: Publisher Site | Google Scholar
M. S. Abbassi, H. Kilani, I. Abid et al., “Genetic background of antimicrobial resistance in multiantimicrobial-resistant Escherichia coli isolates from feces of healthy broiler chickens in Tunisia,” BioMed Research International, vol. 2021, Article ID 1269849, 2021.
View at: Publisher Site | Google Scholar
A. Al Bshabshe, M. R. Joseph, A. A. Awad El-Gied, A. N. Fadul, H. C. Chandramoorthy, and M. E. Hamid, “Clinical relevance and antimicrobial profiling of methicillin-resistant Staphylococcus aureus (MRSA) on routine antibiotics and ethanol extract of mango kernel (Mangifera indica L),” BioMed Research International, vol. 2020, Article ID 4150678, 2020.
View at: Publisher Site | Google Scholar
A. A. Dabbousi, F. Dabboussi, M. Hamze, M. Osman, and I. I. Kassem, “The emergence and dissemination of multidrug resistant Pseudomonas aeruginosa in Lebanon: current status and challenges during the economic crisis,” Antibiotics, vol. 11, no. 5, p. 687, 2022.
View at: Publisher Site | Google Scholar
M. M. Costa, M. Cardo, P. Soares, M. Cara d’Anjo, and A. Leite, “Multi-drug and β-lactam resistance in Escherichia coli and food-borne pathogens from animals and food in Portugal, 2014–2019,” Antibiotics, vol. 11, no. 1, p. 90, 2022.
View at: Publisher Site | Google Scholar
A. M. Ayoub, B. Gutberlet, E. Preis et al., “Parietin cyclodextrin-inclusion complex as an effective formulation for bacterial photoinactivation,” Pharmaceutics, vol. 14, no. 2, p. 357, 2022.
View at: Publisher Site | Google Scholar
M. J. Bottery, J. W. Pitchford, and V. P. Friman, “Ecology and evolution of antimicrobial resistance in bacterial communities,” Multidisplinary journal of Microbial Ecology, vol. 15, no. 4, pp. 939–948, 2021.
View at: Publisher Site | Google Scholar
M. Kumar, D. K. Sarma, S. Shubham et al., “Futuristic non-antibiotic therapies to combat antibiotic resistance: a review,” Frontiers In Microbiology, vol. 16, p. 609459, 2021.
View at: Google Scholar
B. Hetzer, D. Orth-Höller, R. Würzner et al., “Enhanced acquisition of antibiotic-resistant intestinal E coli during the first year of life assessed in a prospective cohort study,” Antimicrobial Resistance & Infection Control, vol. 8, no. 1, pp. 1–13, 2019.
View at: Publisher Site | Google Scholar
A. Mazumdar and V. Adam, “Antimicrobial peptides-an alternative candidates to antibiotics against Staphylococcus aureus and its antibiotic-resistant strains,” Journal of Molecular and Clinical Medicine, vol. 4, no. 1, pp. 1–17, 2021.
View at: Publisher Site | Google Scholar
X. Gao, Z. Wang, X. Li et al., “A new Lactobacillus gasseri strain HMV18 inhibits the growth of pathogenic bacteria,” Food Science and Human Wellness, vol. 11, no. 2, pp. 247–254, 2022.
View at: Publisher Site | Google Scholar
S. Zorrilla, B. Monterroso, M. Á. Robles-Ramos, W. Margolin, and G. Rivas, “FtsZ interactions and biomolecular condensates as potential targets for new antibiotics,” Antibiotics, vol. 10, no. 3, p. 254, 2021.
View at: Publisher Site | Google Scholar
S. Akermi, S. Smaoui, K. Elhadef et al., “Cupressus sempervirens essential oil: exploring the antibacterial multitarget mechanisms, chemcomputational toxicity prediction, and safety assessment in zebrafish embryos,” Molecules, vol. 27, no. 9, p. 2630, 2022.
View at: Publisher Site | Google Scholar
R. Tardugno, A. Serio, C. Purgatorio, V. Savini, A. Paparella, and S. Benvenuti, “Thymus vulgarisL. essential oils from Emilia Romagna Apennines (Italy): phytochemical composition and antimicrobial activity on food-borne pathogens,” Natural Product Research, vol. 36, no. 3, pp. 837–842, 2022.
View at: Publisher Site | Google Scholar
T. Liu, J. Kang, and L. Liu, “Thymol as a critical component of Thymus vulgaris L essential oil combats Pseudomonas aeruginosa_ by intercalating DNA and inactivating biofilm,” LWT, vol. 136, article 110354, 2021.
View at: Publisher Site | Google Scholar
P. Parsaei, M. Bahmani, N. Naghdi, M. Asadi-Samani, and M. Rafieian-Kopaei, “A review of therapeutic and pharmacological effects of thymol,” Der Pharmacia Lettre, vol. 8, no. 2, pp. 150–154, 2016.
View at: Google Scholar
A. I. Foudah, F. Shakeel, M. H. Alqarni et al., “Determination of thymol in commercial formulation, essential oils, traditional, and ultrasound-based extracts of Thymus vulgaris and Origanum vulgare using a greener HPTLC approach,” Molecules, vol. 27, no. 4, p. 1164, 2022.
View at: Publisher Site | Google Scholar
N. B. Rathod, P. Kulawik, F. Ozogul, J. M. Regenstein, and Y. Ozogul, “Biological activity of plant-based carvacrol and thymol and their impact on human health and food quality,” Trends in Food Science & Technology, vol. 116, pp. 733–748, 2021.
View at: Publisher Site | Google Scholar
A. K. Pandey, M. L. Chávez-González, A. S. Silva, and P. Singh, “Essential oils from the genus Thymus as antimicrobial food preservatives: progress in their use as nanoemulsions-a new paradigm,” Trends in Food Science & Technology, vol. 111, pp. 426–441, 2021.
View at: Publisher Site | Google Scholar
F. Z. Radi, M. Bouhrim, H. Mechchate et al., “Phytochemical analysis, antimicrobial and antioxidant properties of Thymus zygis L. and Thymus willdenowii Boiss. essential oils,” Plants, vol. 11, no. 1, p. 15, 2021.
View at: Publisher Site | Google Scholar
L. H. Wang, Z. H. Zhang, X. A. Zeng, D. M. Gong, and M. S. Wang, “Combination of microbiological, spectroscopic and molecular docking techniques to study the antibacterial mechanism of thymol against Staphylococcus aureus: membrane damage and genomic DNA binding,” Analytical and Bioanalytical Chemistry, vol. 409, no. 6, pp. 1615–1625, 2017.
View at: Publisher Site | Google Scholar
H. Lade, S. H. Chung, Y. Lee et al., “Thymol reduces agr-mediated virulence factor phenol-soluble modulin production in Staphylococcus aureus,” BioMed Research International, vol. 2022, Article ID 8221622, 2022.
View at: Publisher Site | Google Scholar
I. Sellem, A. Chakchouk-Mtibaa, H. Zaghden, S. Smaoui, K. Ennouri, and L. Mellouli, “Harvesting season dependent variation in chemical composition and biological activities of the essential oil obtained from _Inula graveolens_ (L.) grown in Chebba (Tunisia) salt marsh,” Arabian Journal of Chemistry, vol. 13, no. 3, pp. 4835–4845, 2020.
View at: Publisher Site | Google Scholar
K. Güven, E. Yücel, and F. Cetintaş, “Antimicrobial activities of fruits of Crataegus and Pyrus species,” Pharmaceutical Biology, vol. 44, no. 2, pp. 79–83, 2006.
View at: Publisher Site | Google Scholar
M. Chandrasekaran and V. Venkatesalu, “Antibacterial and antifungal activity of _Syzygium jambolanum_ seeds,” Journal of Ethnopharmacology, vol. 91, no. 1, pp. 105–108, 2004.
View at: Publisher Site | Google Scholar
April 2022, https://www.ncbi.nlm.nih.gov/.
April 2022, https://www.uniprot.org.
April 2022, https://swissmodel.expasy.org.
A. Waterhouse, M. Bertoni, S. Bienert et al., “SWISS-MODEL: homology modelling of protein structures and complexes,” Nucleic Acids Research, vol. 46, pp. W296–W303, 2018.
View at: Publisher Site | Google Scholar
P. Benkert, M. Biasini, and T. Schwede, “Toward the estimation of the absolute quality of individual protein structure models,” Bioinformatics, vol. 27, no. 3, pp. 343–350, 2011.
View at: Publisher Site | Google Scholar
April 2022, http://www.ebi.ac.uk/thornton-srv/databases/ProFunc/.
April 2022, https://pubchem.ncbi.nlm.nih.gov/.
April 2022, https://www.drugbank.ca/.
April 2022, http://www.molecular-networks.com/online_demos/corina_demo.
J. C. M. Borges, K. Haddi, E. E. Oliveira et al., “Mosquiticidal and repellent potential of formulations containing wood residue extracts of a neotropical plant, _Tabebuia heptaphylla_,” Industrial Crops and Products, vol. 129, pp. 424–433, 2019.
View at: Publisher Site | Google Scholar
https://www.vegahub.eu/.
http://www.swissadme.ch/.
http://www.ibmh.msk.su/PASS/.
A. Lagunin, A. Stepanchikova, D. Filimonov, and V. Poroikov, “PASS: prediction of activity spectra for biologically active substances,” Bioinformatics, vol. 16, no. 8, pp. 747-748, 2000.
View at: Publisher Site | Google Scholar
A. Escobar, M. Perez, G. Romanelli, and G. Blustein, “Thymol bioactivity: a review focusing on practical applications,” Arabian Journal of Chemistry, vol. 1, no. 12, pp. 9243–9269, 2020.
View at: Publisher Site | Google Scholar
M. H. Alqarni, A. I. Foudah, A. Alam, M. A. Salkini, P. Alam, and H. S. Yusufoglu, “Novel HPTLC-densitometric method for concurrent quantification of linalool and thymol in essential oils,” Arabian Journal of Chemistry, vol. 14, no. 2, article 102916, 2021.
View at: Publisher Site | Google Scholar
V. Kuete, “Thymus vulgaris,” Medicinal spices and vegetables from Africa, vol. 1, pp. 599–609, 2017.
View at: Publisher Site | Google Scholar
H. Mith, E. Yayi-Ladékan, S. D. Sika Kpoviessi et al., “Chemical composition and antimicrobial activity of essential oils of Ocimum basilicum, Ocimum canum and Ocimum gratissimum in function of harvesting time,” Journal of Essential Oil Bearing Plants, vol. 19, no. 6, pp. 1413–1425, 2016.
View at: Publisher Site | Google Scholar
M. Khan, S. T. Khan, M. Khan, A. A. Mousa, A. Mahmood, and H. Z. Alkhathlan, “Chemical diversity in leaf and stem essential oils of Origanum vulgare L. and their effects on microbicidal activities,” AMB Express, vol. 9, no. 1, pp. 1–15, 2019.
View at: Publisher Site | Google Scholar
A. Ranjbaran, G. Kavoosi, Z. Mojallal-Tabatabaei, and S. K. Ardestani, “The antioxidant activity of Trachyspermum ammi essential oil and thymol in murine macrophages,” Biocatalysis and Agricultural Biotechnology, vol. 20, article 101220, 2019.
View at: Publisher Site | Google Scholar
J. Hadian, H. Esmaeili, F. Nadjafi, and A. Khadivi-Khub, “Essential oil characterization of _Satureja rechingeri_ in Iran,” Industrial Crops and Products, vol. 61, pp. 403–409, 2014.
View at: Publisher Site | Google Scholar
S. Laquale, P. Avato, M. P. Argentieri, M. G. Bellardi, and T. D’Addabbo, “Nematotoxic activity of essential oils from Monarda species,” Journal of Pest Science, vol. 91, no. 3, pp. 1115–1125, 2018.
View at: Publisher Site | Google Scholar
B. Salehi, A. P. Mishra, I. Shukla et al., “Thymol, thyme, and other plant sources: health and potential uses,” Phytotherapy Research, vol. 32, no. 9, pp. 1688–1706, 2019.
View at: Publisher Site | Google Scholar
K. Kachur and Z. Suntres, “The antibacterial properties of phenolic isomers, carvacrol and thymol,” Critical Reviews in Food Science and Nutrition, vol. 60, no. 18, pp. 3042–3053, 2020.
View at: Publisher Site | Google Scholar
S. Tariq, S. Wani, W. Rasool et al., “A comprehensive review of the antibacterial, antifungal and antiviral potential of essential oils and their chemical constituents against drug- resistant microbial pathogens,” Microbial Pathogenesis, vol. 134, p. 103580, 2019.
View at: Publisher Site | Google Scholar
P. Schnitzler, “Essential oils for the treatment of herpes simplex virus infections,” Chemotherapy, vol. 64, no. 1, pp. 1–7, 2019.
View at: Publisher Site | Google Scholar
Y. Li, J. M. Wen, C. J. Du et al., “Thymol inhibits bladder cancer cell proliferation via inducing cell cycle arrest and apoptosis,” Biochemical and Biophysical Research Communications, vol. 491, no. 2, pp. 530–536, 2017.
View at: Publisher Site | Google Scholar
A. L. Dawidowicz and M. Olszowy, “Does antioxidant properties of the main component of essential oil reflect its antioxidant properties? The comparison of antioxidant properties of essential oils and their main components,” Natural Product Research, vol. 28, no. 22, pp. 1952–1963, 2014.
View at: Publisher Site | Google Scholar
S. C. Heghes, L. Filip, O. Vostinaru et al., “Essential oil-bearing plants from Balkan Peninsula: promising sources for new drug candidates for the prevention and treatment of diabetes mellitus and dyslipidemia,” Frontiers in Pharmacology, vol. 11, p. 989, 2020.
View at: Publisher Site | Google Scholar
S. Gavliakova, Z. Biringerova, T. Buday et al., “Antitussive effects of nasal thymol challenges in healthy volunteers,” Respiratory Physiology & Neurobiology, vol. 187, no. 1, pp. 104–107, 2013.
View at: Publisher Site | Google Scholar
R. I. Ozolua, D. I. Umuso, D. O. Uwaya, A. A. Modugu, S. O. Oghuvwu, and J. Olomu, “Evaluation of the anti-asthmatic and antitussive effects of aqueous leaf extract of Ocimum gratissimum in rodents,” Journal Of Applied Research On Medicinal And Aromatic Plants, vol. 5, pp. 412–2167, 2016.
View at: Google Scholar
A. Komaki, F. Hoseini, S. Shahidi, and N. Baharlouei, “Study of the effect of extract of Thymus vulgaris on anxiety in male rats,” Journal of Traditional and Complementary Medicine, vol. 6, no. 3, pp. 257–261, 2016.
View at: Publisher Site | Google Scholar
M. Asadbegi, P. Yaghmaei, I. Salehi, A. Komaki, and A. Ebrahim-Habibi, “Investigation of thymol effect on learning and memory impairment induced by intrahippocampal injection of amyloid beta peptide in high fat diet- fed rats,” Metabolic Brain Disease, vol. 32, no. 3, pp. 827–839, 2017.
View at: Publisher Site | Google Scholar
Y. Zhang, Y. Niu, Y. Luo et al., “Fabrication, characterization and antimicrobial activities of thymol-loaded zein nanoparticles stabilized by sodium caseinate-chitosan hydrochloride double layers,” Food Chemistry, vol. 142, pp. 269–275, 2014.
View at: Publisher Site | Google Scholar
M. Mahboubi and N. Kazempour, “Chemical composition and antimicrobial activity of Satureja hortensis and Trachyspermum copticum essential oil,” Iranian Journal Of Microbiology, vol. 3, no. 4, pp. 194–200, 2011.
View at: Google Scholar
M. Zviely and M. Li, “Ocimene a versatile floral ingredient,” Perfumer & Flavorist, vol. 38, pp. 42–45, 2013.
View at: Google Scholar
B. Ghatak, S. B. Ali, B. Tudu, P. Pramanik, S. Mukherji, and R. Bandyopadhyay, “Detecting Ocimene in mango using mustard oil based quartz crystal microbalance sensor,” Sensors and Actuators B: Chemical, vol. 284, pp. 514–524, 2019.
View at: Publisher Site | Google Scholar
D. S. Tshibangu, A. Matondo, E. M. Lengbiye et al., “Possible effect of aromatic plants and essential oils against COVID-19: review of their antiviral activity,” Journal of Complementary and Alternative Medical Research, vol. 11, no. 1, pp. 10–22, 2020.
View at: Publisher Site | Google Scholar
C. Cavaleiro, L. Salgueiro, M. J. Gonçalves, K. Hrimpeng, J. Pinto, and E. Pinto, “Antifungal activity of the essential oil of Angelica major against Candida, Cryptococcus, Aspergillus and dermatophyte species,” Journal of Natural Medicines, vol. 69, no. 2, pp. 241–248, 2015.
View at: Publisher Site | Google Scholar
F. H. Afshar, F. Maggi, R. Iannarelli, K. Cianfaglione, and M. B. Isman, “Comparative toxicity of _Helosciadium nodiflorum_ essential oils and combinations of their main constituents against the cabbage looper, _Trichoplusia ni_ (Lepidoptera),” Industrial Crops and Products, vol. 98, pp. 46–52, 2017.
View at: Publisher Site | Google Scholar
A. Ghasemi Pirbalouti, A. Izadi, F. Malek Poor, and B. Hamedi, “Chemical composition, antioxidant and antibacterial activities of essential oils from Ferulago angulata,” Pharmaceutical Biology, vol. 54, no. 11, pp. 2515–2520, 2016.
View at: Publisher Site | Google Scholar
S. H. Lone, K. A. Bhat, H. M. Bhat et al., “Essential oil composition of _Senecio graciliflorus_ DC: comparative analysis of different parts and evaluation of antioxidant and cytotoxic activities,” Phytomedicine, vol. 21, no. 6, pp. 919–925, 2014.
View at: Publisher Site | Google Scholar
M. A. Lewis, E. B. Russo, and K. M. Smith, “Pharmacological foundations of cannabis chemovars,” Planta Medica, vol. 84, no. 4, pp. 225–233, 2018.
View at: Publisher Site | Google Scholar
G. Di Rauso Simeone, A. Di Matteo, M. A. Rao, and C. Di Vaio, “Variations of peel essential oils during fruit ripening in four lemon (Citrus limon (L.) Burm. F.) cultivars,” Journal of the Science of Food and Agriculture, vol. 100, no. 1, pp. 193–200, 2020.
View at: Google Scholar
B. Teixeira, A. Marques, C. Ramos et al., “Chemical composition and bioactivity of different oregano (Origanum vulgare) extracts and essential oil,” Journal of the Science of Food and Agriculture, vol. 93, no. 11, pp. 2707–2714, 2013.
View at: Publisher Site | Google Scholar
M. Paw, T. Begum, R. Gogoi, S. K. Pandey, and M. Lal, “Chemical composition of Citrus limon L. Burmf peel essential oil from North East India,” Journal of Essential Oil Bearing Plants, vol. 23, no. 2, pp. 337–344, 2020.
View at: Publisher Site | Google Scholar
N. Puvača, J. Milenković, T. Galonja Coghill et al., “Antimicrobial activity of selected essential oils against selected pathogenic bacteria: in vitro study,” Antibiotics, vol. 10, no. 5, p. 546, 2021.
View at: Publisher Site | Google Scholar
M. Pateiro, F. J. Barba, R. Domínguez et al., “Essential oils as natural additives to prevent oxidation reactions in meat and meat products: a review,” Food Research International, vol. 113, pp. 156–166, 2018.
View at: Publisher Site | Google Scholar
T. R. de Oliveira Ramalho, M. T. P. de Oliveira, A. L. de Araujo Lima, C. R. Bezerra-Santos, and M. R. Piuvezam, “Gamma-terpinene modulates acute inflammatory response in mice,” Planta Medica, vol. 81, no. 14, pp. 1248–1254, 2015.
View at: Publisher Site | Google Scholar
G. Ben Salha, R. Herrera Díaz, O. Lengliz, M. Abderrabba, and J. Labidi, “Effect of the chemical composition of free-terpene hydrocarbons essential oils on antifungal activity,” Molecules, vol. 24, no. 19, p. 3532, 2019.
View at: Publisher Site | Google Scholar
P. C. Lin, J. J. Lee, and I. J. Chang, “Essential oils from Taiwan: chemical composition and antibacterial activity against Escherichia coli,” Journal of Food and Drug Analysis, vol. 24, no. 3, pp. 464–470, 2016.
View at: Publisher Site | Google Scholar
A. El Asbahani, K. Miladi, W. Badri et al., “Essential oils: from extraction to encapsulation,” International Journal of Pharmaceutics, vol. 483, no. 1-2, pp. 220–243, 2015.
View at: Publisher Site | Google Scholar
M. Huo, X. Cui, J. Xue et al., “Anti-inflammatory effects of linalool in RAW 264.7 macrophages and lipopolysaccharide-induced lung injury model,” Journal of Surgical Research, vol. 180, no. 1, pp. e47–e54, 2013.
View at: Publisher Site | Google Scholar
A. M. Api, D. Belsito, S. Bhatia et al., “RIFM fragrance ingredient safety assessment, Linalool, CAS registry number 78-70-6,” Food and Chemical Toxicology, vol. 82, pp. S29–S38, 2015.
View at: Publisher Site | Google Scholar
I. Pereira, P. Severino, A. C. Santos, A. M. Silva, and E. B. Souto, “Linalool bioactive properties and potential applicability in drug delivery systems,” Colloids and Surfaces B: Biointerfaces, vol. 171, pp. 566–578, 2018.
View at: Publisher Site | Google Scholar
B. K. Lee, A. N. Jung, and Y. S. Jung, “Linalool ameliorates memory loss and behavioral impairment induced by REM-sleep deprivation through the serotonergic pathway,” Biomolecules & Therapeutics, vol. 26, no. 4, pp. 368–373, 2018.
View at: Publisher Site | Google Scholar
Y. Higa, H. Kashiwadani, M. Sugimura, and T. Kuwaki, “Orexinergic descending inhibitory pathway mediates linalool odor-induced analgesia in mice,” Scientific Reports, vol. 11, no. 1, pp. 1–12, 2021.
View at: Publisher Site | Google Scholar
S. Mehri, M. A. Meshki, and H. Hosseinzadeh, “Linalool as a neuroprotective agent against acrylamide-induced neurotoxicity in Wistar rats,” Drug and Chemical Toxicology, vol. 38, no. 2, pp. 162–166, 2015.
View at: Publisher Site | Google Scholar
M. F. Lemos, M. F. Lemos, H. P. Pacheco et al., “Seasonal variation affects the composition and antibacterial and antioxidant activities of Thymus vulgaris,” Industrial Crops and Products, vol. 95, pp. 543–548, 2017.
View at: Publisher Site | Google Scholar
C. Moisa, A. Lupitu, G. Pop et al., “Variation of the chemical composition of Thymus vulgaris essential oils by phenological stages,” Revista de Chimie, vol. 70, no. 2, pp. 633–637, 2019.
View at: Publisher Site | Google Scholar
B. Tohidi, M. Rahimmalek, and H. Trindade, “Review on essential oil, extracts composition, molecular and phytochemical properties of Thymus species in Iran,” Industrial Crops and Products, vol. 134, pp. 89–99, 2019.
View at: Publisher Site | Google Scholar
G. Khalili, A. Mazloomifar, K. Larijani, M. S. Tehrani, and P. A. Azar, “Solvent-free microwave extraction of essential oils from _Thymus vulgaris L. and Melissa officinalis L,” Industrial Crops and Products, vol. 119, pp. 214–217, 2018.
View at: Publisher Site | Google Scholar
J. A. Llorens-Molina and S. Vacas, “Effect of drought stress on essential oil composition of Thymus vulgaris L. (chemotype 1, 8-cineole) from wild populations of Eastern Iberian Peninsula,” Journal of Essential Oil Research, vol. 29, no. 2, pp. 145–155, 2017.
View at: Publisher Site | Google Scholar
H. S. Aljabeili, H. Barakat, and H. A. Abdel-Rahman, “Chemical composition, antibacterial and antioxidant activities of thyme essential oil (Thymus vulgaris),” Food and Nutrition Sciences, vol. 9, no. 5, pp. 433–446, 2018.
View at: Publisher Site | Google Scholar
A. A. Khan and M. S. Amjad, “GC-MS analysis and biological activities of Thymus vulgaris and Mentha arvensis essential oil,” Turkish Journal of Biochemistry, vol. 44, no. 3, pp. 388–396, 2019.
View at: Google Scholar
M. Moghaddam and L. Mehdizadeh, “Chemical composition and antifungal activity of essential oil of Thymus vulgaris grown in Iran against some plant pathogenic fungi,” Journal of Essential Oil Bearing Plant, vol. 23, no. 5, pp. 1072–1083, 2020.
View at: Publisher Site | Google Scholar
M. E. O’Sullivana, Y. Songa, R. Greenhousea et al., “Dissociating antibacterial from ototoxic effects of gentamicin C-subtypes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 51, pp. 32423–32432, 2020.
View at: Publisher Site | Google Scholar
M. E. Badawy, G. I. K. Marei, E. I. Rabea, and N. E. Taktak, “Antimicrobial and antioxidant activities of hydrocarbon and oxygenated monoterpenes against some foodborne pathogens through in vitro and in silico studies,” Pesticide Biochemistry and Physiology, vol. 158, pp. 185–200, 2019.
View at: Publisher Site | Google Scholar
J. V. Vermaas, G. J. Bentley, G. T. Beckham, and M. F. Crowley, “Membrane permeability of terpenoids explored with molecular simulation,” The Journal of Physical Chemistry B, vol. 122, no. 45, pp. 10349–10361, 2018.
View at: Publisher Site | Google Scholar
M. P. Alamoti, B. B. Gilani, R. Mahmoudi et al., “Essential oils from indigenous Iranian plants: a natural weapon vs. multidrug-resistant Escherichia coli,” Microorganisms, vol. 10, no. 1, p. 109, 2022.
View at: Publisher Site | Google Scholar
Q. Benameur, T. Gervasi, V. Pellizzeri et al., “Antibacterial activity of Thymus vulgaris essential oil alone and in combination with cefotaxime against bla ESBL producing multidrug resistant Enterobacteriaceae isolates,” Natural Product Research, vol. 33, no. 18, pp. 2647–2654, 2019.
View at: Publisher Site | Google Scholar
Y. Toubi, F. Abrigach, S. Radi et al., “Synthesis, antimicrobial screening, homology modeling, and molecular docking studies of a new series of Schiff base derivatives as prospective fungal inhibitor candidates,” Molecules, vol. 24, no. 18, p. 3250, 2019.
View at: Publisher Site | Google Scholar
Z. Xiang, “Advances in homology protein structure modeling,” Current Protein and Peptide Science, vol. 7, no. 3, pp. 217–227, 2006.
View at: Publisher Site | Google Scholar
J. D. O. Giacoppo, J. B. Carregal, M. C. Junior, E. F. D. Cunha, and T. C. Ramalho, “Towards the understanding of tetrahydroquinolines action in Aedes aegypti: larvicide or adulticide?” Molecular Simulation, vol. 43, no. 2, pp. 121–133, 2017.
View at: Publisher Site | Google Scholar
A. Robinson and A. M. Van Oijen, “Bacterial replication, transcription and translation: mechanistic insights from single-molecule biochemical studies,” Nature Reviews Microbiology, vol. 11, no. 5, pp. 303–315, 2013.
View at: Publisher Site | Google Scholar
H. Cui, M. Bai, Y. Sun, M. A. S. Abdel-Samie, and L. Lin, “Antibacterial activity and mechanism of Chuzhou chrysanthemum essential oil,” Journal of Functional Food, vol. 48, pp. 159–166, 2018.
View at: Publisher Site | Google Scholar
S. H. Kirsch, F. J. Haeckl, and R. Müller, “Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi,” Natural Product Reports, vol. 39, no. 6, pp. 1226–1263, 2022.
View at: Publisher Site | Google Scholar
C. Liang, S. Huang, Y. Geng et al., “A study on the antibacterial mechanism of thymol against Aeromonas hydrophila in vitro,” Aquaculture International, vol. 30, no. 1, pp. 115–129, 2022.
View at: Publisher Site | Google Scholar
C. R. dos Santos Barbosa, J. R. Scherf, T. S. de Freitas et al., “Effect of carvacrol and thymol on NorA efflux pump inhibition in multidrug-resistant (MDR) Staphylococcus aureus strains,” Journal of Bioenergetics and Biomembranes, vol. 53, no. 4, pp. 489–498, 2021.
View at: Publisher Site | Google Scholar
N. T. Lan-Phi and T. T. Vy, “Chemical composition, antioxidant and antibacterial activities of peels' essential oils of different pomelo varieties in the south of Vietnam,” International Food Research Journal, vol. 22, no. 6, p. 2426, 2015.
View at: Google Scholar
A. S. Al-Dhahli, F. A. Al-Hassani, K. M. Alarjani et al., “Essential oil from the rhizomes of the Saudi and Chinese Zingiber officinale cultivars: comparison of chemical composition, antibacterial and molecular docking studies,” Journal of King Saud University-Science, vol. 32, no. 8, pp. 3343–3350, 2020.
View at: Publisher Site | Google Scholar
J. Dai, C. Li, H. Cui, and L. Lin, “Unraveling the anti-bacterial mechanism of Litsea cubeba essential oil against E. coli O157:H7 and its application in vegetable juices,” International Journal of Food Microbiology, vol. 338, p. 108989, 2021.
View at: Publisher Site | Google Scholar
W. De Souza Moura, S. R. de Souza, F. S. Campos et al., “Antibacterial activity of Siparuna guianensis essential oil mediated by impairment of membrane permeability and replication of pathogenic bacteria,” Industrial Crops and Products, vol. 146, article 112142, 2020.
View at: Publisher Site | Google Scholar
M. Vigan, “Essential oils: renewal of interest and toxicity,” European Journal of Dermatology, vol. 20, no. 6, pp. 685–692, 2010.
View at: Publisher Site | Google Scholar
M. Y. Memar, P. Raei, N. Alizadeh, M. A. Aghdam, and H. S. Kafil, “Carvacrol and thymol: strong antimicrobial agents against resistant isolates,” Reviews in Medical Microbiology, vol. 28, no. 2, pp. 63–68, 2017.
View at: Publisher Site | Google Scholar
K. Schönknecht, H. Krauss, J. Jambor, and A. M. Fal, “Treatment of cough in respiratory tract infections-the effect of combining the natural active compounds with thymol,” Wiadomosci lekarskie (Warsaw, Poland: 1960), vol. 69, no. 6, pp. 791–798, 2016.
View at: Google Scholar
A. K. Tyagi, S. Prasad, W. Yuan, S. Li, and B. B. Aggarwal, “Aggarwal, “Identification of a novel compound (β-sesquiphellandrene) from turmeric (Curcuma longa) with anticancer potential: Comparison with curcumin,”,” Investigational New Drugs, vol. 33, no. 6, pp. 1175–1186, 2015.
View at: Publisher Site | Google Scholar
D. Velásquez-Jiménez, D. A. Corella-Salazar, B. S. Zuñiga-Martínez et al., “Phenolic compounds that cross the blood–brain barrier exert positive health effects as central nervous system antioxidants,” Food & Function, vol. 12, no. 21, pp. 10356–10369, 2021.
View at: Publisher Site | Google Scholar
M. Mahanthesh, D. Ranjith, R. Yaligar, R. Jyothi, G. Narappa, and M. Ravi, “Swiss ADME prediction of phytochemicals present in Butea monosperma (Lam.) Taub,” Journal of Pharmacognosy and Phytochemistry, vol. 9, no. 3, pp. 1799–1809, 2020.
View at: Google Scholar
J. H. McKerrow and C. A. Lipinski, “The rule of five should not impede anti-parasitic drug development,” International Journal for Parasitology: Drugs and Drug Resistance, vol. 7, no. 2, pp. 248-249, 2017.
View at: Publisher Site | Google Scholar
M. Mojumdar, M. S. H. Kabir, M. S. Hasan et al., “Molecular docking and pass prediction for analgesic activity of some isolated compounds from Acalypha indica L. and ADME/T property analysis of the compounds,” World Journal of Pharmaceutical Research, vol. 5, no. 7, pp. 1761–1770, 2016.
View at: Google Scholar
R. Flores, X. Jin, J. Chang et al., “LCAT, ApoD, and ApoA1 expression and review of cholesterol deposition in the cornea,” Biomolecules, vol. 9, no. 12, p. 785, 2019.
View at: Publisher Site | Google Scholar
A. Sharanek, P. B. E. Azzi, H. Al-Attrache et al., “Different dose-dependent mechanisms are involved in early cyclosporine a-induced cholestatic effects in hepaRG cells,” Toxicological Sciences, vol. 141, no. 1, pp. 244–253, 2014.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2022 Sarra Akermi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

648

Downloads

535

Citations