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Carvacrol and thymol; Strong antimicrobial agents against resistant isolates

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 Carvacrol and thymol: strong antimicrobial agents
against resistant isolates
Mohammad Y. Memara,b, Parisa Raeic, Naser Alizadehb,d,
Masoud Akbari Aghdama and Hossein Samadi Kafild

Antibiotics have been effective in treatment of infectious diseases, but resistance to

these drugs has led to the severe consequences. In recent years, medicinal herbs have
been used for the prevention and protection against infectious diseases. Thymol and
carvacrol are active ingredients of family Lamiaceae; these components have anti-
bacterial and antifungal effects. In this review, we survey antimicrobial properties of
carvacrol and thymol. Available data from different studies (microbiological, retrieve
from PubMed, and Scopus databases) about antimicrobial affects carvacrol and thymol
was evaluated. Carvacrol and thymol can inhibit the growth of both gram-positive and
gram-negative bacteria. These compounds have antifungal and antibiofilm effects.
Thymol and carvacrol can also be applied as an alternative antimicrobial agent against
antibiotic-resistant pathogenic bacteria. Thus, thymol and carvacrol are recom-
mended for potential medical use; however, more research is required on toxicity
and side-effects of the compounds.
Copyright ß 2017 Wolters Kluwer Health, Inc. All rights reserved.

Reviews in Medical Microbiology 2017, 28:63–68

Keywords: antibacterial, antibiofilm, antifungal, carvacrol, thymol

Introduction Plants are one source of the compounds with anti-

Infectious diseases are common reasons of morbidity and
mortality in the world [1]. Introduction of antibiotics
have had a consequence not only on the management of
infections but also on society by changing morbidity and
mortality [2]. However, the abuse of these compounds has
led to the emergence and increasing of multidrug-
resistant pathogens [3]. The situation is deteriorated by
the increasing the number of antibiotic-resistant patho-
gens and potential to endure after exposure to
antimicrobial agents [4]. As no new drugs have been
introduced to manage antibiotic-resistant pathogens, and
as it seems doubtful that any novel agents will be
established presently, clinicians may become obliged to
administrate some drugs regardless of their complications
[5]. Hence, antibiotic-resistant pathogens are public
health crisis and the need to explore and identify new
compounds with antibacterial properties without toxic
effects on human cells is obvious [6].
microbial activity that provides options of novel
alternative drugs for microbial disease [7]. Essential oils
derived from plants are one of the most important
agricultural products with antimicrobial property [8].
About 3000 essential oils produced by at least 2000 plant
species, which about 300 of them are significant from the
marketing viewpoint [9]. Essential oils and their
constituent small molecules exhibit excellent medicinal
properties and hence may be used against infectious and
noninfectious diseases [10]. Essential oils are definite as
any volatile oil(s) that have strong aromatic components
and that give characteristic odor, flavor, or smell to a
plant. These are the byproducts of plant metabolism and
are frequently referred to as volatile plant secondary
metabolites. Essential oils are found in glandular hairs or
secretory cavities of plant-cell wall and are present as
droplets of juice in the leaves, stems, bark, flowers, roots,
and/or fruits in different plants [11]. Carvacrol and
thymol are the major constituents of the essential oils,

a
Infectious and Tropical Disease Research Center, bStudent Research Committee, cDrug Applied Research Center, and
d
Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
Correspondence to Hossein Samadi Kafil, PhD, Assistant Professor, Drug Applied Research Center, Tabriz University of Medical
Sciences, Tabriz, Iran.
Tel: +98 9127184735; fax: +98 4133364661; e-mail: Kafilhs@tbzmed.ac.ir
Received: 21 October 2016; revised: 2 February 2017; accepted: 7 February 2017

DOI:10.1097/MRM.0000000000000100

ISSN 0954-139X Copyright Q 2017 Wolters Kluwer Health, Inc. All rights reserved. 63
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
64 Reviews in Medical Microbiology 2017, Vol 28 No 2
which belong to the Lamiaceae family of plants including
oregano and thyme [12]. In this study, we review
antimicrobial effects of carvacrol and thymol.
Traditional application
The ancient Egyptians used thymol and carvacrol as
protective agents to preserve the mummies [13]. They
were also used as an active additive in food flavoring,
perfumes, cosmetics, mouthwash, and some of them have
been made for massaging the joints and to treat nail fungi
as topical ointments. Drugs formulated from these
compounds were administered to care for infections of
the mouth and throat and prevent of gingivitis [14].
Thymol
Thymol (also known as 2-isopropyl-5-methylphenol)
(Fig. 1), a phenolic compound present in essential oils, is a
natural monoterpene and carvacrol isomer that extracted
from thyme and the other kinds of plants [15]. Thymol is
less water soluble at neutral pH, but it is as well soluble in
some organic solvents and alcohols [16]. It has been
observed its antioxidant, antispasmodic, antimicrobial,
and anti-inflammatory property [17]. It is a p-cymene
derivative compound and is also identified for the
antiseptic and antimicrobial effects [18]. Some studies
have reported the usage of thymol for anticancer property
[19]. The antioxidant effects of thymol and carvacrol have
been confirmed in several studies, suggesting their
administration as nutritious elements in the improvement
of novel functional foods [20]. Thymol protective
nature against caries and plaques allures the field of
dental drugs [21].
Carvacrol
Carvacrol (5-isopropyl-2-methylphenol), (Fig. 1), is also
monoterpene that found in many plant species such as
thyme and with greater amount in oregano [22].
Fig. 1. Chemical structure of thymol and carvacrol.
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
Carvacrol is significant component of essential oils and
recently has attracted much attention as a result of its
biological properties, such as a wide spectrum of
antimicrobial activity. Because carvacrol exhibits strong
antioxidative properties and both hydrophobic properties
associated with the substituted aromatic ring and
hydrophilic properties associated with the phenolic
OH group, numerous studies report its antioxidative,
anti-inflammatory, antibacterial, antifungal, antiproto-
zoal, anticarcinogenic, antidiabetic, antinociceptive,
cardioprotective, and neuroprotective properties [23].
Antibacterial effect of thymol and
carvacrol
Several studies were reported antibacterial effects of
thymol alone or in combination with other substance
such as carvacrol [24]. These compounds can inhibit
growth of both gram-positive and gram-negative bacteria
[24]. Low toxicity and pleasant smell as well as taste of
thymol show that this material can be used as an additive
to prevent bacterial spoilage [25]. Trombetta et al. [26]
report the antimicrobial efficacy of thymol against
Staphylococcus aureus and Escherichia coli. Some researchers
speculated that the antibacterial mechanism of thymol
may consequence, at least partly, from a perturbation of
the lipid fraction of the bacterial plasma membrane,
resulting in changes of membrane permeability and in the
escape of intracellular content [27,28]. Lambert, et al.
exhibited antibacterial effect of thymol and carvacrol
against Pseudomonas aeruginosa and S. aureus as a result of
disruption in membrane integrity, which further affects
the pH homeostasis and balance of inorganic ions [27].
Therefore, antibacterial property of carvacrol and thymol
is dependent to their capability to permeabilize,
depolarize, and disruption of the cytoplasmic membrane.
Gas chromatographic mass spectrometric examination
indicated thymol is major essential oil of Monarda punctata.
The results of study carried by Li et al. [29] indicated that
Streptococcus pyogenes, E. coli, and Streptococcus pneumonia
were the most susceptible to thymol, whereas methicillin-
resistant S. aureus was reported to be the most resistant
to the essential oil with relatively higher Minimum
Inhibitory Concentration (MIC) and Minimum
bactericidal concentration (MBC) values. The disk
diffusion method data show thymol is most effective
against Brochothrix thermosphacta (Inhibition Zone:
39.7 mm) followed by Listeria monocytogenes and Salmo-
nella thyphimurium (Inhibition Zone: 35.6 and 33.3 mm,
respectively). The MIC and MBC values (0.25 and
0.5 mg/ml, respectively) were the same for L. mono-
cytogenes, S. thyphimurium, and E. coli O157:H7.
Pseudomonas fluorescens was the least inhibited by thymol
(MIC and MBC ranging from 1 to 1.5 mg/ml). These
components could be probable options to be applied as
 Carvacrol and thymol: strong antimicrobial agents Memar et al. 65

natural alternatives for further usage in food conservation
to hold up or inhibit the bacterial increase and for
protection and to expand the shelf existence of the food
products. However, the verification of antibacterial
effects and organoleptic impact of these essential oils in
foodstuffs require assessing [30]. Results of several studies
were confirmed bactericidal effects of thymol and
carvacrol against of pathogens and food spoilage bacteria
(Table 1) [24,31–39].
the susceptibility of S. typhimurium to ampicillin,
tetracycline, penicillin, bacitracin, erythromycin, and
novobiocin and resistance of S. pyogenes to erythromycin
[24]. On the basis of these data, the authors recommended
that thymol in combination with specific antimicrobial
drugs may be an efficient alternative option to treat
infections.

The antibacterial efficacy of carvacrol and thymol in
combination with other antibacterial compounds on
gram-negative and gram-positive organism were eval-
uated in some studies. The results of these studies will be
affected by the methods for detection of synergy effects.
For example Hamoud et al. [40], reported checkerboard
data indicate indifferent interaction against gram-positive
and synergy against gram-negative bacteria, whereas
time-kill analyses advocate synergistic achievement in
diverse combinations against both types of bacteria.
Combinations of thymol and carvacrol with antibacterial
(azithhromycin, clarithromycin, minocycline, and tige-
cycline) using checkerboard indicted achievement a
synergism in the great majority of cases [41]. Thymol and
carvacrol were found to be highly efficient in increasing
Effect of thymol and carvacrol on biofilm
formation
Biofilm biomass is a mixture of exopolysaccharides,
proteins, DNA, and extracellular matrix that has the
stabilizing role of biofilm construction [42]. Bacteria in a
biofilm are much more resistant to antibiotics than to
planktonic status [43]. The plant derivatives can effect on
microbial biofilms [44]. Several studies described thymol
and carvacrol inhibited growth of preformed biofilm and
interfered with biofilm formation during planktonic
growth [45,46]. Nostro et al. [46] reported carvacrol and
thymol attenuated biofilm formation of S. aureus and
Staphylococcus epidermidis strains on polystyrene microtitre
plates and they suggested these oils repressed expansion of

Table 1. Results of varies study that assessed antimicrobial effects of thymol and carvacrol.

Compound Microorganism Main findings References

Thymol, carvacrol,
cinnamaldehyde, and
eugenol alone or
combined
Cinnamaldehyde,
thymol, and carvacrol
alone or their
combinations
Oregano oil, carvacrol,
and thymol
Carvacrol and thymol
Lippia sidoides and
thymol
Thymol
Carvacrol and thymol
Thymol
Carvacrol and thymol
Eugenol, carvacrol,
thymol and
cinnamaldehyde
Streptococcus mutans
ATCC25175
S. sanguis, S. mitis, and S. milleri
Peptostreptococcus anaerobius
ATCC 4956, Prevotella buccae,
P. oris, and P. intermedia
S. typhimurium
Methicillin-susceptible and
methicillin-resistant
staphylococci (MSS and MRS)
E. coli
Enterococcus faecalis
L. monocytogenes
Shigella sonnei and S. flexneri
C. albicans
P. digitatum and P. italicum
Tetracycline-resistant S.
Typhimurium and E. coli,
penicillin-resistant S. aureus
and erythromycin-resistant S.
pyogenes
Use of eugenol and thymol or eugenol and carvacrol [31]
combinations would be suitable in the management of
oral infections
MIC of cinnamaldehyde, thymol, and carvacrol for [32]
S. typhimurium were 200, 400, and 400 mg/l,
respectively. By their paired combinations, MIC of
cinnamaldehyde, thymol and carvacrol could be
decreased from 200, 400, and 400 mg/l to 100, 100, and
100 mg/l, respectively
All S. aureus and S. epidermidis strains reported susceptible [33]
to these compound with no significant difference
between MRS and MSS strains
Carvacrol and thymol could inhibit the growth of E. coli. [34]
The antibacterial property was related to their capacity to
permeabilize and depolarize the bacterial membrane
Thymol kill microorganisms present in biofilms [35]
Thymol could potentially be applied to control L. [36]
monocytogenes biofilms in food processing
Antibacterial effects of thymol and carvacrol against [37]
Sheigella spp.
Thymol may be used as a potential antifungal therapy in the [38]
future
The application of these essential oils in the citrus packing [39]
lines could be considered as appropriate alternatives to
reduce the use of synthetic fungicides
Natural antimicrobials were able to significantly reduce the [24]
MIC of antibiotics in a different group of resistant bacteria

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

66 Reviews in Medical Microbiology 2017, Vol 28 No 2
preformed biofilm and obstructed with the biofilm
development during planktonic phase. El Abed et al. [47]
also described anti-adherence and antibiofilm effects of
terpenes and pointed out the excellent effectiveness of
eugenol, carvone, and carveol, which could characterize
candidates in the management of P. aeruginosa biofilm.
Thymol can also prevent the first stages of biofilm
formation and interfering with the formation of mature
biofilms as a result of the inhabitation of metabolic
activity for biofilms. All of these events may lead to major
membrane and blockage the production of viable
filamentous forms during the early steps of biofilm
formation. As biofilms are multifactorial event, the several
mechanisms of thymol (terpenes) perhaps effect on
diverse stages in their development [48].
Antifungal effect by thymol and carvacrol
Direct antifungal agents resistance is still a chief unease
when antifungal treatment failure is considered [49].
There are limits antifungal drugs available for treatment,
drug-resistant strains are also evidence of biofilm
infections and side-effects of prescription drugs will have
problems in the prevention and treatment of fungal
infections [50]. Several studies described antifungal effects
of thymol and carvacrol against fungal pathogens.
Antifungal effect of thymol and carvacrol investigated
against Penicillium digitatum and Penicillum italicum. Both
essential oils were effective in inhibiting fungal growth;
thymol was more effective than carvacrol [39].
Guo et al. [51] indicated antifungal activity of thymol
against clinical isolates of fluconazole susceptible and
nonsusceptible Candida albicans and high percentage of
synergism effects of thymol in combination with
amphotericin B.
Thymol and carvacrol because of the restrain of ergosterol
biosynthesis and the disturbance of membrane totality
shows potent fungicidal efficacy against Candida isolates
[52]. Effective fungicidal properties of carvacrol and
thymol against different plant pathogens were also
formerly reported by Kordali et al. [53].
Development of herbicides helps reduce factors such as
pollution and environmental degradation; in this regard,
natural herbicides can be effective. Essential oils and
monoterpenes compounds showed antifungal activity in
the treatment of mucormycosi [54,55].
Thymol is lipophilic compound, that alone or with
carvacrol, can change the cell membrane fluidity and
permeability [56]. In addition to this, the compound can
changes the cell membrane in fungi such as C. albicans by
the affect the function of the cell membrane enzymes that
catalyzes the synthesis of the cell wall polysaccharide
Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.
compounds such as b -glucan and inhibit the growth of
cells [57,58]. The results of electron microscopy showed
that thymol and carvacrol change the morphogenesis of
the envelope of C. albicans [58].
Carvacrol was also effective in reducing the growth of
Botrytis cinerea in berry and grapes; in grapes, 97%
inhibition was related to the higher doses of carvacrol
[59,60]. In addition to this, carvacrol was effective in
reducing the spore germinates and mycelium growth of
B. cinerea inoculated in grapes [59].
Other researchers showed the effect of monoterpenoid-
son the conidial germination and mycelial growth of B.
cinerea [61]. Also, Tsao and Zhou [61] reported that
0.25 mg/ml of thymol had an inhibitory effect on the
increase of mycelium of Monilinia fructicola, also on the
solid media, was 100% inhibited conidial germination of
the bacteria.
Toxicity issue
Essential oils affect the various active molecules in the cell
for different purposes, that, main purpose is the
cytoplasmic membrane [62]. Disruption of the per-
meability of the cell membrane leads to the loss of cell
function such as the electron transport chain, also affected
the eukaryotic cells [63]. Toxicity to eukaryotic cells is
responsible for undesirable side-effects for a host, such as
inflammation, corrosion, cell sensitivity, acute toxicity to
organs, and limits the use of essential oils as medicinal use
[52]. It is difficult to detect the toxicity of essential oils
because the toxicity varies based on the compounds and
depends on various factors [64]. A study showed that
thymol and carvacrol had the most toxic in concen-
trations of 36–49 mg/l, which are less toxic than some
combination of essential oils [65]. There is less risk of
accumulation of body tissues. Therefore, it is suggested
possible medical use thymol and carvacrol, but more
research must be done on this issue.
Conclusion
Several studies have shown antibacterial and antifungal
property of the thymol and carvacrol. Thymol and
carvacrol can be applied as an alternative antimicrobial
agent against antibiotic-resistant pathogenic bacteria and
C. albicans. It is necessary for further precise detection of
thymol and carvacrol safety to determine the optimal dose
of these substances for human cells. Results of various
studies proposed replace of traditional medicines instead
of synthetic drugs, which has more side-effects. In this
review, reported information about the effects of
antibacterial, antifungal, and antibiofilm thymol and
 Carvacrol and thymol: strong antimicrobial agents Memar et al.
carvacrol that provides a better view about the thymol and
carvacrol. More studies using bacterial strains isolated
from patients treated with these compounds needs to
be done.
Acknowledgements
This study was supported by Drug Applied Research
Center, Tabriz University of Medical Sciences, Tabriz,
Iran.
Conflicts of interest
The authors declare no conflicts of interest.
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