Chemistry Biodiversity - 2023 - El Ghallab - Clove Buds Volatile Compounds Inhibitory Activity On Mycobacterium Growth

doi.org/10.1002/cbdv.
202300895 Research Article

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Clove Buds Volatile Compounds: Inhibitory Activity on

Mycobacterium Growth and Molecular Docking on Mmr
Efflux Pump Drug Resistance
Yassine El Ghallab,*[a] Jamal Jamal Eddine,[b] Achraf Aainouss,[c] My Driss El Messaoudi,[c]
Mohamed Dakir,[b] and Sanae Derfoufi[a]
Syzygium aromaticum is used in traditional and modern H37Rv strain was sensitive to all volatile samples at concen-
medicine for its various and outstanding pharmacological tration range between 10 and 100 μg/mL. The NPF of ethanol
properties. Here, we studied the chemical composition of extract was the best inhibitor with a MIC = 10 μg/mL. The in
hexane extract and non-polar fractions (NPF) obtained from the silico study revealed a strong binding affinity between eugenol
maceration and fractionation of clove buds, in order to evaluate and Mmr EP protein ( 8.1 Kcal/mol), involving two binding
their in vitro antimycobacterial activity, as well as their contribu- modes of hydrogen bond and π-alkyl interactions. The non-
tion against efflux pump (EP) resistance through molecular polarity character of clove volatile constituents, and their
docking experiments. The gas chromatography-mass spectrom- potential additive or synergistic effects could be responsible for
etry (GC–MS) analysis of the volatile profiles revealed the the antimycobacterial activity. In addition, these findings
presence of eugenol, followed by eugenyl acetate, and β- suggest the benefic effect of eugenol in the management of
caryophyllene as common major compounds. According to mycobacterium drug resistance, whether as potential inhibitor
Resazurin microtiter assay (REMA), Mycobacterium tuberculosis of Mmr drug EP, or modulator during combination therapy.
Introduction bacteria, the damage produced was attributed to the major

compound, eugenol.[9] The latter is well-known by its pharmaco-
Clove with the scientific name of Syzygium aromaticum (L.) logical characteristics and safety.[10] The world Health Organiza-
Merr. and L.M. Perry, belongs to the Myrtaceae family. The clove tion (WHO) has developed an acceptable dietary intake value of
tree is originally from Indonesia, and mainly cultivated in many 2.5 mg/kg per day.[11–13]
countries such as Island of Zanzibar, Pemba, and Brazil.[1] Clove Tuberculosis is the deadliest human microbial pathogen
is a popular flavor and fragrance spice, widely appreciated in during the history of infectious diseases, which is still invincible
cooking thanks to its spicy power, aromatic and pungent smell due to the increasing prevalence of resistant strains to the first-
and taste, as well as in traditional and modern medicine for its line and second-line antitubercular drugs. The mycobacterium
various and outstanding pharmacological properties.[2–4] Clove is envelope is quite thick and lipid due to the abundance of
an antimicrobial agent against many bacteria and fungi, also mycolic acids, thus leading to diminish hydrophilic molecules
used as a preservative, antiseptic, stimulant, and carminative. permeability, and the emergence of antibiotics resistance.[14,15]
Clove enters in the treatment of diarrhea, intestinal worms and Many studies have associated the improved antituberculosis
other digestive disorders. Dentists have used clove essential oil activity to the increased lipophilicity of a molecule, as it is the
as an oral anesthetic and to disinfect root canals.[5–8] The case of many promising antituberculosis candidates.[16–18] Strong
bactericidal effect of the essential oil passes through its action antimycobacterial activities of essential oil components have
on the cell envelope that plays a fundamental role in the life of been reported, especially, for carvacrol and thymol monoterpe-
noids (MIC = 2.02 and 0.78 μg/mL, respectively).[19] Indeed, the
[a] Y. El Ghallab, S. Derfoufi hydrophobic character of bioactive compounds leads to
Laboratory of Drugs Sciences, Biomedical Research and Biotechnology, optimize their passage through the highly lipophilic mycomem-
Faculty of Medicine and Pharmacy, Hassan II University of Casablanca, B.P. brane, and therefore, making the cells more permeable.
9154, Casablanca 20250, Morocco
Sergio et al.[20] found a minimum inhibitory value of 25 μg/
E-mail: elghallabyassine@gmail.com
yassine.elghallab-etu@etu.univh2c.ma ml for each eugenol and clove essential oil against the
[b] J. J. Eddine, M. Dakir pathogenic strain of Mycobacterium tuberculosis H37Rv. Although
Laboratory of Organic Synthesis, Extraction and Valorization, Department a value of 12.5 μg/ml was marked by this essential oil against
of Chemistry, Faculty of Sciences Ain Chock, Hassan II University of isoniazid (INH), rifampicin (RIF), ethambutol (EMB), or strepto-
Casablanca, B.P. 5366 Casablanca 20000, Morocco
mycin (STR) resistant strains. Recently, a MIC = 125 μg/ml of
[c] A. Aainouss, M. D. El Messaoudi
essential oil was required to prevent the growth of H37Rv
Laboratory of Mycobacteria and Tuberculosis, Institut Pasteur of Morocco, 1
place Louis Pasteur, 20360 Casablanca, Morocco strain.[21] The antimycobacterial activity was tested for many
Supporting information for this article is available on the WWW under medicinal plants. However, most of them focused only on using
https://doi.org/10.1002/cbdv.202300895 crude extracts that contain a complex mixture of bioactive
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doi.org/10.1002/cbdv.202300895
compounds. Only alcoholic and aqueous clove extracts from Table 1. Volatile compounds of hexane extract and fractions from clove
flower and bud parts were tested on Mycobacterium tuberculosis buds
H37Ra strain. Sivakumar et al.[22] have reported a growth Compound [a] RT [b] RT [c] %
inhibition at 200 μg/mL for the ethanolic extract, but no Hexane NPF- NPF-
inhibition for the aqueous extract. extract Ethyl Ethanol
The over expression of EP has constituted another disturb- acetate extract
extract
ing mechanism of mycobacteria resistance as a result of the
inhibition of antibiotics accumulation by the transmembrane Benzyl acetate 13.96 4.87 0.04 nd nd
hydrophobic proteins.[23–27] For this reason, EP proteins have Methyl Salicylate 15.35 5.14 0.06 0.06 nd
been considered promising targets to diminish the frequency of p-Chavicol 17.85 5.56 0.20 0.28 0.30
intrinsic drugs resistance. Several efflux transporters are Eugenol 22.70 6.42 49.33 47.24 49.49
involved in drug resistance of mycobacteria.[25,28] Mmr (rv3065) Copaene 23.49 6.59 0.31 0.54 0.32
is an EP belonging to small multidrug resistance (SMR) family
β-Caryophyl- 25.36 6.92 18.34 17.69 13.51
conferring resistance to many antimicrobial agents such as lene
ethidium bromide (EtBr) and erythromycin.[29] It has been α-Humulene 26.82 7.15 3.59 2.58 2.21
reported that the deletion of lfrA and Mmr homologue
γ-Muurolene 27.91 7.27 0.49 0.37 0.26
rendered the strains more susceptible to EtBr and fluoroquino-
α-Muurolene 28.83 7.29 1.32 nd nd
lones among others.[29] Verapamil (VER) is an EP inhibitor that
β-Selinene 28.37 7.36 nd 0.11 0.11
has also been shown to potentiate the effect of bedaquiline on
Mycobacterium tuberculosis.[30] Concerning plant-based efflux Eugenyl acetate 29.70 7.53 23.59 21.61 24.89
pump inhibitors, certain alkaloids have been proven effective, Trans (E)-Cadina- 30.18 7.63 0.17 0.04 0.08
1,4-diene
as the case of reserpine (RES) which is an antagonist of the P-gp
Caryophyllene 32.16 7.99 0.87 4.59 3.06
EP, that may completely reverse the drug efflux in multidrug
epoxide
resistant bacteria.[29] In the best of our knowledge, scarcely are
Allo-Aromaden- 34.42 8.29 0.37 2.02 1.87
studies that had been focused on the evaluation of the drene epoxide
potential action of clove chemicals against the multidrug Benzyl Benzoate 38.90 8.98 0.12 0.12 0.16
resistance caused by EP systems.
Ethyl palmitate 47.09 10.06 nd 0.11 0.26
In this context, non-polar clove mixtures seem to respond
Ethyl linoleate 51.47 10.89 nd 0.04 0.23
to the hydrophobic criteria required for invasion of the
[a] [b]
characteristic mycobacterial wall thanks to the lipidic nature of Order of elution on BP-5 capillary column. RT : Retention time on DB-5
capillary column.[33] RT [c]: Retention time on BP-5 capillary column. NPF:
the mycomembrane and to the resistant hydrophobic trans-
Non-polar fraction. nd: Not detected.
membrane proteins. Therefore, we investigated the chemical
composition of hexane extract and NPF obtained by liquid-
liquid fractionation of ethanol and ethyl acetate extracts from
cloves buds, we evaluated as well their in vitro effect against eugenol and eugenyl acetate with 71.56 and 8.99 %, respec-
Mycobacterium tuberculosis H37Rv strain. Molecular docking tively. In addition, all other constituents were different except
study was performed to reveal the potential contribution of the caryophyllene oxide (1.67 %). Differently, Bagavan et al.[32]
major identified volatile compounds for the treatment of identified chavibetol as the major compound of the flower bud
multidrug resistant bacteria, through the determination of their hexane extract, followed by eugenyl acetate, and caryophyllene.
affinity and binding modes with Mmr EP target, as one of the Interestingly, these main constituents are similar to those
drug resistance mechanisms in Mycobacterium tuberculosis. detected in the essential oil from clove buds previously
reported.[10] On the other hand, studies on the volatile profile of
polar clove extracts are scarce. The NPF of ethyl acetate extract
Results and Discussion of clove buds contains 15 volatile compounds which represent
97.40 % of the identified constituents. Whereas, a total of 14
Volatile compounds of clove fractions chemical ingredients recovers 96.75 % of the whole fraction
composition from alcoholic extract. The volatile profiles of the
The hexane, ethyl acetate and ethanol extracts prepared from both fractions are similar to that of hexane extract, except for
clove buds maceration yielded to 10.5, 13.9 and 14.7 %, caryophyllene oxide, of which this time is more abundant after
respectively. The fractionation yields were 57.3 % from ethyl β-caryophyllene and eugenyl acetate (Table 1). These constitu-
acetate extract and 46 % from ethanol extract. The GC/MS ents, in addition to eugenol as the common major compound
investigation of clove hexane extract revealed 14 identified represent 91.13 % for NPF of ethyl acetate extract, and 90.95 %
compounds which recover a total of 98.81 % (Table 1). Eugenol, for NPF ethanol extract (Figure 1). The α-humulene and
eugenyl acetate, β-caryophyllene and α-humulene are the main aromadendrene epoxide were also detected in significant
constituents, and represent a total of 94.85 % (Figure 1). On one amounts of around 2 %.
hand, few studies have reported the volatile profile of clove
hexane extract. Nassar et al.[31] showed the predominance of
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Research Article
Figure 1. Chromatograms of clove buds volatile compounds.
Chem. Biodiversity 2023, 20, e202300895 (3 of 7)

doi.org/10.1002/cbdv.202300895
Research Article
doi.org/10.1002/cbdv.202300895
Antimycobacterial activity conformations realised by the major identified compounds

within Mmr EP protein. Eugenol showed the potent binding
The hexane extract and NPFs from clove ethyl acetate and affinity with Mmr protein comparing to eugenyl acetate and β-
ethanol extracts were able to prevent the mycobacterial growth caryophyllene. The minimum binding energy of the best
of the pathogenic strain H37Rv. This may be explained by the eugenol conformation within the target protein was equal to
hydrophobic nature of the chemical constituents able to invade that of VER standard, which suggests its inhibitory action on
the lipid mycomembrane and make the cells more permeable. Mmr drug efflux pump (Table 3).
The NPF of alcoholic extract was the best inhibitor of H37Rv Eugenol and both standards occupied different binding
strain, five time more potent than the hexane extract, and ten sites, the first one was located inside the receptor, and the
time more potent than the NPF of ethyl acetate extract others were stabilized in different extreme locations. This
(Table 2). This difference could be attributed to the proportion indicates the potential modulator effect of eugenol in the case
of the main identified constituents. It was observed that of a combination treatment with antibiotics. Similar to VER and
eugenyl acetate was more abundant in the most active fraction. RES standards, eugenol established two hydrogen bonds of
Aryadne et al.[21] found that eugenyl acetate was more effective close contacts of 2.89 and 2.22 Å, inside the pocket residues of
to prevent the growth of nontuberculous mycobacteria (NTM) Mmr, as a result of the presence of hydroxy group that allowed
than eugenol. It was also more active than eugenol against interactions between oxygen atom and Ser 73 amino acid
sensible Mycobacterium tuberculosis isolate (MIC of 7.8 μg/mL donor group, and between hydrogen atom and Ala 69 amino
vs. 250 μg/mL, respectively), as well as against some clinical acid acceptor group. Another binding mode of π-alkyl was
isolates resistant to one or more first-line antituberculosis mainly implicated in the stability of eugenol-Mmr docked
drugs.[21] Moreover, the possibility of additive and/or synergistic complex by eight hydrophobic interactions with several amino
effects between the chemical constituents should be taken into acid residues. Additionally, alkyl-alkyl and π-cation binding
consideration, as combined natural products lead to the modes were also attributed to the complex stability generated
reduction of active concentrations and the improvement of by the standards with the protein target (Figure 2) (Figure S1,
interaction between antimicrobial agents and targets. A syner- Supporting Information). A docking analysis revealed that
gistic effect of eugenol combined with RIF, INH, EMB, and quercetin could act as a non-antibiotic adjuvant by inhibiting
pyrazinamide (PZD) has been reported on sensible and multi- Mmr drug efflux pump in Mycobacterium tuberculosis.[41] There-
drug-resistant mycobacteria.[21] Given that eugenol predom- fore, our finding suggests the benefic effect of eugenol in the
inates the chemical composition of all analyzed clove mixtures, management of mycobacterium drug resistance either as a
its contribution in the antituberculosis activity is of great potential inhibitor of Mmr drug efflux pump, or as a modulator
interest. Some authors conferred the antimicrobial effect of this during combination therapy.
phenylpropanoid to the hydroxy function that tends to inhibit
the enzymatic action via protein binding.[34–36] Others have
described eugenol mechanism of action on bacterial cells Conclusions
through the disruption of the cytoplasmic membrane becoming
thereby more permeable and affecting the transport of ions We investigated the volatile profile of hexane extract and NPFs
and ATP.[37–40] As the case against the bacterium salmonella from alcoholic and ethyl acetate extracts of clove buds. The
typhi; the antibacterial activity of eugenol occurred through the GC–MS analyses detected eugenol, eugenyl acetate, and β-
alteration of membrane permeability, then ion leakage and caryophyllene as the major common constituents. The extract
significant loss of cellular contents, such changes lead to the and the both fractions were active against Mycobacterium
cell death.[37] tuberculosis H37Rv strain, and expressed a moderate to good
Molecular docking on Mmr drug efflux pump Table 3. Binding energies and active residues in the Mmr docked
complexes with major compounds.
Compound Mmr
The molecular docking study against EP drug resistance in
mycobacteria was based on the generation of the best binding BE Residues
Eugenol 8.1 Ala A69, A72; Ser A73; Trp A131; Phe A155; Tyr
A101, A115; Leu A111;
Table 2. Inhibitory activity of clove extract and fractions on Mycobacterium Eugenyl 5.9 Ala A28, A117, B117; Arg A29, A121 B29; Glu
tuberculosis H37Rv. acetate A113; His B120; Met A116
Sample MIC (μg/ml) β-caryophyl- 5.4 Ala B74; Leu B130
lene
Hexane extract 50
VER 8.1 Gln A125, B105; His A120; Arg B109; Glu B113;
NPF-Ethanol extract 10
Thr B110; Pro A122; Leu B163; Ala A119
NPF-Ethyl acetate extract 100
RES 9.7 Arg A25; Arg A29; Arg A109; Pro B122; Leu
INH 0.01 A163; Ala A18, A44
NPF: Non-polar fraction. INH: Isoniazid. BE: Binding energy (Kcal/mol).
Research Article
doi.org/10.1002/cbdv.202300895
Figure 2. Binding sites of the best docking conformations of eugenol (purple), RES (cyan) and VER (orange) within Mmr protein, amino acid residues and
hydrogen bonds (red dashed line) involved in eugenol-Mmr complex.
growth inhibitory effect, in particular for NPF of ethanol extract. Experimental Section
This activity seems to be influenced by the non-polarity
character of the identified constituents which is in harmony Chemicals and instruments
with the lipidic nature of the mycomembrane. Therefore, further Middlebrook broth base (M7H9), albumin, dextrose and catalase
investigations should be carried out on their potential use as (ADC) enrichment, polymyxin B, amphotericin B, nalidixic acid,
alternative antimycobacterials. Additionally, the molecular dock- trimethoprim and azlocillin (PANTA), and resazurin sodium salt
ing study revealed a strong binding affinity between eugenol were purchased from Sigma–Aldrich and HiMedia Laboratories. All
other chemicals and solvents were of analytical grade. The analysis
and Mmr target protein as one of overexpressed efflux pumps
of volatile compounds was performed by GC–MS unit, consisted on
in Mycobacterium tuberculosis. The eugenol-Mmr docked com- a Shimadzu GC-2010 gas chromatograph with BP-5 capillary
plex included two binding modes of hydrogen bond and π-alkyl column (30 m×0.25 mm i.d., film thickness 0.25 μm; SGE, Ltd.), and
interactions. This interesting finding suggests that eugenol coupled to Shimadzu QP2010 Plus mass spectrometer (software
could be beneficial for the prevention of drug resistance version 2.50 SU1).
emergence as a potential Mmr efflux pump inhibitor or as a
modulator during combination therapy. Preparation of clove fractions
The clove buds were purchased from local spice market in
Casablanca, Morocco, and were stored in clear poly bags. Extracts
were prepared by three independent macerations using solvents
with varying polarity of ethanol, ethyl acetate, and hexane. 100 g of
fine powder of dried clove buds were placed in 1 L of each
corresponding solvent for three days. The mixture was stored in
dark at room temperature, then the extract was filtered, concen-
Research Article
doi.org/10.1002/cbdv.202300895
trated in rotary evaporator. The process was repeated until the dimensions were adjusted to encompass the whole protein. The
residue was exhausted. Then the ethanol and ethyl acetate extracts molecular docking program AutoDock Vina (version 1.1.2)[44] was
were submitted to water-hexane fractionations using ampoule used to perform the docking experiments. The Lamarckian Genetic
decantation. The hexane-soluble fraction obtained from each crude Algorithm was used to explore the best conformation space for the
extract was concentrated in vacuo to give the corresponding NPF ligand with the least binding energy.
that was stored at 4 °C.
GC/MS analysis Author Contributions

The identification of volatile compounds was carried out by GC–MS.
The oven temperature was programmed as described for GC Y. E. and A. A. Investigation. Y. E. Formal analysis, Software,
analysis; transfer line temperature, 300 °C; ion source temperature, Visualization, Project administration, Writing- Original draft
200 °C; carrier gas, helium, adjusted to a linear velocity of
preparation, Writing- Reviewing and Editing. Y. E. and J. J. E.
36.5 cm s 1; split ratio, 1 : 40; ionization energy, 70 eV; scan range, 40
400 u; scan time, 1 s. Chemical constituents were performed on Data interpretation. Y. E. and M. D. Conceptualization. M. D. E.,
their retention time (RT) on the BP-5 capillary column, compared J. J. E. and S. D. Resources. M. D. E. and S. D. Validation. S. D. and
with those published in the literature,[33] and confirmed by M. D. Supervision.
comparing their mass spectra with a data bank (Shimadzu
corporation library and NIST 05 database/ChemStation data
system).
Acknowledgements
Mycobacterium H37Rv inhibitory test Thanks to Achraf Abdou from Faculty of Sciences Ain Chock,
Hassan II University of Casablanca, for technical help.
The sensitivity of mycobacterium H37Rv strain to the prepared
hexane extract and NPFs from clove buds was estimated by REMA
according to Palomino et al.[42] with slight modification. The REMA
plate method was performed in Middlebrook 7H9 medium Conflict of Interests
containing Middlebrook broth base, 0,05 % Tween 80, 0,2 % glycerol
and 2,4 % PANTA, and supplemented with 10 % albumin, dextrose The authors declare no conflict of interest.
and catalase (ADC) enrichment. The tested samples and INH
standard were prepared by serial two-fold dilutions with culture
medium, and a volume of 100 μl was used. The inoculum was
prepared from fresh Middlebrook 7H9 medium by dilution 1 : 100, Data Availability Statement
and 100 μl was added to 96-well plate. The plates were covered
and incubated at 37 °C in normal atmosphere. After 4 days of The data that support the findings of this study are available in
incubation, 30 μl of resazurin solution (0.02 %) was added to growth
the supplementary material of this article.
control without antibiotic, and assessed for color development of
the indicator. The change in color from blue to pink indicates the
reduction of resazurin due to the growth of mycobacteria. Then Keywords: antimycobacterial activity · drug efflux pump ·
resazurin indicator was added to each well and the plate was re- natural products · syzygium aromaticum · terpenoids
incubated overnight at 37 °C. The MIC was defined as the lowest
concentration of sample that prevented the appearance of pink
color.
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Chemistry Biodiversity - 2023 - El Ghallab - Clove Buds Volatile Compounds Inhibitory Activity On Mycobacterium Growth

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doi.org/10.1002/cbdv.

202300895 Research Article

Clove Buds Volatile Compounds: Inhibitory Activity on

Introduction bacteria, the damage produced was attributed to the major

© 2023 Wiley-VHCA AG, Zurich, Switzerland

Figure 1. Chromatograms of clove buds volatile compounds.

Chem. Biodiversity 2023, 20, e202300895 (3 of 7)

Antimycobacterial activity conformations realised by the major identified compounds

NPF: Non-polar fraction. INH: Isoniazid. BE: Binding energy (Kcal/mol).

GC/MS analysis Author Contributions

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