Essential Oils and Future Antibiotics: New Weapons against Emerging‘Superbugs’?

Abstract

Antibiotic resistance is emerging at an alarming rate, outpacing current research and development efforts to combat this trend. As a result, many infectious diseases have become difficult to treat; in some cases, no treatment options exist. The search for new antibiotics must accelerate to avoid returning to the ‘pre-antibiotic’ era. Ancient remedies, including essential oils and their components, have been explored on a limited basis as a source of new antimicrobials. Many are known to possess significant antimicrobial activity against a wide range of microorganisms. Elucidation of the mechanism of action of these compounds may lead to identification new antibiotic targets. Such targets, once identified, may represent biosynthetic or regulatory pathways not currently inhibited by available drugs. Novel drugs and targets are vital for continued control of infectious diseases worldwide.

Full text

Volume 1 • Issue 2 • 1000105
J Anc Dis Prev Rem
ISSN:JADPR an open access journal
Open AccessReview Article
Journal of Ancient Diseases
& Preventive Remedies
Boire et al., J Anc Dis Prev Rem 2013, 1:2
http://dx.doi.org/10.4172/jadpr.1000105
Keywords: Essential oils; Antibiotic resistance; New antibiotics
Introduction
Not long ago, we thought we had conquered infectious disease.
e scourge of mankind had been vanquished by the discovery of
antibiotics.
“…we can look forward with condence to a considerable degree
of freedom from infectious diseases at a time not too far in the future.
Indeed…it seems reasonable to anticipate that within some measurable
time…all the major infections will have disappeared….” [1].
e discovery of antibiotics revolutionized medicine; the increasing
emergence of antibiotic resistance threatens to return medicine to
the pre-antibiotic era. Recently, the US Centers for Disease Control
sounded an alarm regarding emerging antibiotic resistance and the
threat to public health.
“CRE are nightmare bacteria. ey pose a triple threat. First, they’re
resistant to all or nearly all antibiotics, even some of our last-resort drugs.
Second, they have high mortality rates. ey kill up to half of people
who get serious infections with them. And third, they can spread their
resistance to other bacteria.” [2].
To combat emerging antibiotic resistance and the rise of ‘superbugs’,
new drugs are needed. However, research and development for new
antimicrobial agents is lagging far behind the rate at which bacteria
are developing resistance. As a result, many infectious diseases once
easily cured have now become increasingly dicult to treat. So where
are new antimicrobials to be found? Perhaps by looking to the past, we
may discover signicant science behind the ‘myths’ of ancient remedies;
science which could lead to the development of new antibiotics and
other drugs.
Ancient Remedies: A History
For thousands of years, aromatic oils have been used to relieve a
wide variety of human maladies including bronchitis, pneumonia,
pharyngitis, diarrhea, periodontal disease, wounds, and numerous
other illnesses. Many traditions surrounding the use of these oils are
buried in antiquity, passed down orally from master to student until the
origin of specic treatments were lost to the ages. In antiquity, medicinal
oils were derived from aromatic plants and resins by extraction into
other fatty oils such as olive oil and used as a mixture. e earliest
*Corresponding author: Nicole Parrish, Department of Pathology, Division of
Microbiology, The Johns Hopkins University, 600 North Wolfe Street, Meyer B1-
193, Baltimore, MD, 21287,USA, Tel: 410-955-5077; Fax: 410-614-8087; E-mail:
nparrish@jhmi.edu
Received
May 02, 2013; Accepted May 30, 2013; Published June 03, 2013
Citation: Boire NA, Riedel S, Parrish NM (2013) Essential Oils and Future
Antibiotics: New Weapons against Emerging ‘Superbugs’? J Anc Dis Prev Rem 1:
105. doi:10.4172/jadpr.1000105
Copyright: © 2013 Boire NA, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited.
Essential Oils and Future Antibiotics: New Weapons against Emerging
‘Superbugs’?
Nicholas A Boire
1
, Stefan Riedel
2
and Nicole M Parrish
2
*
1
The Johns Hopkins University, Bloomberg School of Public Health, Baltimore, Maryland, USA
2
Department of Pathology, Division of Microbiology, The Johns Hopkins University, School of Medicine, Baltimore, Maryland, USA
Abstract
Antibiotic resistance is emerging at an alarming rate, outpacing current research and development efforts to
combat this trend. As a result, many infectious diseases have become difcult to treat; in some cases, no treatment
options exist. The search for new antibiotics must accelerate to avoid returning to the ‘pre-antibiotic’ era. Ancient
remedies, including essential oils and their components, have been explored on a limited basis as a source of new
antimicrobials. Many are known to possess signicant antimicrobial activity against a wide range of microorganisms.
Elucidation of the mechanism of action of these compounds may lead to identication new antibiotic targets. Such
targets, once identied, may represent biosynthetic or regulatory pathways not currently inhibited by available drugs.
Novel drugs and targets are vital for continued control of infectious diseases worldwide.
recorded use of aromatic oils dates back to 4,500 B.C. in Egypt [3]. e
ancient Egyptians recognized that oils could be used in treating illness,
including infection and inammation. So valuable were these oils, that
King Tutankhamun was entombed with roughly 350 liters of aromatic
oil including cedarwood, frankincense, and myrrh [3]. Myrrh is one of
the earliest and well known of the aromatic oils. References to myrrh
abound in antiquity. e ancient Hebrews referred to myrrh as ‘holy oil’
which was more valuable than gold. e ancient Egyptians referred to
myrrh as ‘the tears of Horus’. Myrrh is derived from the resin of a woody
shrub of the genus, Commiphora, which grows in hot, arid climates.
In ancient Sumer, myrrh was used for treating parasitic infections and
periodontal disease. e Greek physician, Dioscorides, used myrrh
for bronchial and other infections including the skin [4]. Myrrh was
oen combined with frankincense, aromatic oil used in antiquity to
treat infectious diseases and inammation. Like myrrh, frankincense
is member of a resinous family of plants (Burseraceae) commonly
found in arid regions of the Middle East and north-east Africa [5,6].
e use of frankincense and myrrh is mentioned numerous times in
biblical and other ancient texts [7]. ese oils, alone or in combination,
were used extensively for the treatment of wounds, inammation,
cystitis, rheumatic joints, skin sores, bleeding, fungal infections, burns,
pharyngitis, syphilis, and leprosy [8,9].
Other cultures across the globe have long-standing, medical practices
which incorporate the use of aromatic oils and other plant-based
therapies, including those found in the Americas, Australia, and the Far
East such as the Ayurvedic, Unani, and Chinese traditions. Among the
more well-recognized remedies still in use today from North and South
America and Australia are purple coneower (Echinacea purpurea),
cat’s claw (Uncaria tomentosa), and eucalyptus (Eucalyptus globulus)

Citation: Boire NA, Riedel S, Parrish NM (2013) Essential Oils and Future Antibiotics: New Weapons against Emerging ‘Superbugs’? J Anc Dis Prev
Rem 1: 105. doi:10.4172/jadpr.1000105
Page 2 of 5
Volume 1 • Issue 2 • 1000105
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ISSN:JADPR an open access journal
[4]. Ayurvedic traditions include the use of camphor (Cinnamomum
camphora) and cardamomum (Elettaria cardamomum) [4]. China’s use
of herbal medicine dates as far back as 3000 B.C., when the mythological
and legendary ruler Shen Nong Shi (or Shennong) taught humans the
use of medicinal plants. His cumulative work, ‘Shennong Bencao Jing’,
is considered one of the earliest medical collections in China [10]. By
500 A.D. the use of aromatic oils had spread throughout most of Asia
Minor, and the Mediterranean, spreading along with the Roman and
later the Persian Empires [11]. Commonly used aromatic oils included
those derived from thyme, clove, rosemary, lavender, and cinnamon.
Today, the term ‘essential oils’ is used to describe the mixtures
derived from aromatic medicinal plants using conventional techniques
such as distillation and chromatographic separation. ese oils continue
to be used for the treatment of infectious disease and inammation in
traditional medicine across the globe. ey are administered orally,
topically, or via aromatherapy, depending on historical use and chemical
composition which for many essential oils has been determined. As a
result, a signicant amount of toxicity data is available for not only the
oils but also the individual components such that many are generally
regarded as safe (GRAS) by the FDA. GRAS status has permitted the
use of essential oils as avoring agents in food and as additives to
cosmetics, perfumes, and cleaning products.
Ancient Remedies: e Science
Essential oils are derived from a variety of natural sources
including plants or components of plants such as owers, leaves, bark,
roots, berries, seeds and/or fruit. ese oils are complex mixtures of
chemicals, and include various alcohols, aldehydes, terpenes, ethers,
ketones, phenols, and oxides. Many essential oils have limited solubility
in aqueous solutions and form emulsions with non-ionic surfactants.
Previous investigators have reviewed the eect of essential oils, their
components and antimicrobial activity [12-17]. However, few studies
have determined the antimicrobial-specic mechanism(s) of action of
various essential oils or their components [18,19].
Since essential oils are complex mixtures of compounds, it is likely the
observed antimicrobial activity is due to inhibition or interaction with
multiple targets in the cell [20,21]. However, many essential oils exert
non-specic antimicrobial eects due to the hydrophobic properties of
the mixtures and components. For instance, the hydrophobic character
of many essential oils facilitates entry into cell membranes leading
to alteration in architecture, leakage of cell contents, and eventually
death [22-26]. In 2009, Fisher and Phillips demonstrated uptake of
Citrus sinensis and Citrus bergamia oils into Enterococcus faecium and
E. faecalis resulting in multiple membrane-related changes: a 2- or 40-
fold increase in membrane permeability, a decrease in intracellular pH,
the loss of membrane potential, and a reduction in ATP concentration
[25]. is is not surprising given that many essential oils contain high
concentrations of phenolic compounds including carvacrol, thymol,
and eugenol. Phenols are known to disrupt cell membranes resulting
in the dissolution of the proton motive force and a subsequent decrease
in ATP synthesis [27-29]. Inhibition of ATP synthesis may also result
from essential oil-mediated alteration of protein-protein interactions
in the cell membrane or direct binding of oil components, especially
cyclic hydrocarbons, to lipophilic regions of membrane-bound proteins
[28,30]. Diminished ATP levels would necessarily lead to reduction
in other energy-dependent cellular processes including synthesis of
enzymes and toxins. For example, previous studies have demonstrated
a signicant decrease in the amount of diarrheal toxin detected in
Bacillus cereus when exposed to carvacrol. e authors hypothesized
that the decrease in toxin detection may be connected to the decrease
in ATP production which is required not only for toxin synthesis but
also export [31].
Although the spectrum of activity for most essential oils is relatively
broad, as would be expected with a mechanism of action related to
membrane disruption, evidence is emerging which suggests more
specic targets may exist. Such specic targets may vary between
organisms, thus explaining the more narrow range of activity of some
essential oils and/or components. In such cases, specicity may be
related to individual essential oil components. Recently, investigators
attempted to determine the mechanism of action of cold-pressed
Valencia orange oil against methicillin-resistant Staphylococcus aureus
(MRSA) [32]. Microarray data showed a 24-fold increase in expression
of cwrA following exposure to the oil. Interestingly, upregulation of
cwrA was also demonstrated following exposure to known cell wall-
active antibiotics such as penicillin G, oxacillin, phosphomycin,
imipenem, and vancomycin suggesting a similar mechanism of
action [33-35]. Other specic eects of citrus oil on MRSA include
increased expression of penicillin-binding–protein-4 (PBP 4), involved
in peptidoglycan synthesis, and genes in the dltABCD operon. is
operon controls alanylation of teichoic acids of the cell wall which may
play a role in autolysin activity of S. aureus [32]. Autolysin activity was
also suggested by Carson and coworkers who noted that tea tree oil
resulted in release of membrane-bound, cell wall autolytic enzymes
leading to cell lysis and death [21].
Specic targets have also been implicated by the dierential activity
of essential oils observed against various microorganisms [12]. For
instance, multiple studies have shown that essential oils work well
against a number of Gram-positive bacteria, with only moderate to little
eect on Gram-negative organisms [12]. Some investigators postulated
that Gram-negative organisms were intrinsically more resistant to the
eects of essential oils due to the presence of the outer membrane which
provides an additional permeability barrier [36]. However, susceptibility
of Gram-negative bacteria can vary by genus and species. Aeromonas
hydrophila, a Gram-negative bacteria commonly found in water,
was highly susceptible to the eects of essential oils via an unknown
mechanism; Enterobacter aerogenes was inhibited by cinnamon oil via
interaction with various amino acid decarboxylases [37-40]. In these
examples, the dierence in susceptibility may be due to the presence or
absence of the essential oil-specic target versus other Gram-positive or
–negative bacteria; alternatively, the specic target may be present but
exist in a dierent isoform resulting in altered susceptibility.
Other specic mechanisms of action have been identied which
involve quorum sensing, cellular division, sporulation, stress responses
and eux pumps. Many Gram-positive and –negative bacterial
organisms communicate in a complex interplay known as ‘quorum
sensing’ which is used to regulate various cellular functions ranging
from biolm formation and swarming to expression of virulence
factors and toxins [12]. It has been suggested that interruption of
these bacterial communication networks may inhibit attachment
and invasion by some pathogens exploiting an alternative pathway
for antimicrobial development as compared with current antibiotics
[41, 42]. Interference of quorum sensing has been demonstrated by a
number of plant extracts, including garlic, which resulted in signicant
inhibition of biolm formation in P. aeruginosa [43,44]. is inhibition
not only appeared to be concentration dependent, but also illustrated
properties of competitive binding as suggested by structure-activity
relationship studies [43,44]. Biolm formation was also inhibited
in S. aureus and Salmonella enterica serovar typhimurium following

Citation: Boire NA, Riedel S, Parrish NM (2013) Essential Oils and Future Antibiotics: New Weapons against Emerging ‘Superbugs’? J Anc Dis Prev
Rem 1: 105. doi:10.4172/jadpr.1000105
Page 3 of 5
Volume 1 • Issue 2 • 1000105
J Anc Dis Prev Rem
ISSN:JADPR an open access journal
exposure to carvacrol, a monoterpene found in many essential oils
[45]. ese ndings suggest inhibition of quorum sensing and biolm
formation may provide unique and as yet, unexplored targets for
development of new antibiotics. However, other new drug targets may
exist, which disrupt cellular division and sporulation as observed with
lamentous fungi exposed to various essential oils [46]. In 2006, Pawar
and aker [45] demonstrated that cinnamon bark oil was highly active
against Aspergillus niger resulting in reduced production of hyphae
and spores and in some cases complete inhibition of growth. e
underlying mechanism(s) for these observations were not determined.
However, previous investigators identied a correlation between
inhibition of sporulation and cellular respiration versus growth [47].
Specically, essential oils such as citron and lavender signicantly
inhibited sporulation and cellular respiration, with little eect on
growth, whereas oils from cinnamon bark and lemongrass decreased
growth, with little to no eect on sporulation or cellular respiration
[47]. e eect on cellular respiration has implications for additional
drug targets, especially those involving energy-dependent processes
such as eux of various macromolecules as seen with bacterial eux
pumps. Bacterial eux pumps are responsible for multidrug resistance
in a number of bacteria including the AcrAB-TolC eux system in
the Enterobacteriaceae and the MexAB-OprM system in Pseudomonas
aeruginosa [12]. Recent evidence suggests that these eux mechanisms
may in part be responsible for the decreased susceptibility of many
Gram-negative organisms to plant-derived phytochemicals and
essential oils. However, some oils such as falcarindiol, derived from
Levisticum ocinale, and the geraniol containing Helicrysum italicum
have demonstrated anti-eux activity especially in combination
with ciprooxacin and chloramphenicol, respectively, against Gram-
negative bacteria [48,49].
Other common components of essential oils with specic
antimicrobial activity are alcohols and aldehydes. Alcohols, especially
the terpene alcohols, have signicant bactericidal activity against a
wide range of microorganisms. is bactericidal activity is thought to
occur via a number of mechanisms including denaturation of proteins,
dehydration of bacterial cells, or solvation of bacterial cell membranes
[50,51]. In comparison, aldehydes are thought to interfere with reactions
involving electron transfer, especially when conjugated to a carbon-
carbon double bond. Such an electronegative molecular arrangement
would result in interference with a large number of biological reactions
of central metabolism (e.g. respiration and carbon cycling) resulting in
rapid cell death [51].
Ancient Remedies: Combining the Old and the New?
Research and development of new antibiotics decreased
signicantly in the 1970’s when the need for new drugs was thought
to be negligible since infectious diseases were becoming a concern
of the past. As a result, when new antibiotics were needed (e.g. when
resistance emerged), pharmaceutical companies merely modied
existing antibiotics via slight structural alterations. is approach
was more economical than developing a completely new drug,
especially at a time when the prevailing perception was that humanity
had conquered infectious disease [52]. Today, infections have been
documented which are resistant to all known drugs; treatment is oen
problematic and unsuccessful [53]. Unfortunately, antibiotics of ‘last
resort’ are oen used, including drugs previously abandoned due to
overt toxicity or serious side eects [54]. Yet even this approach fails to
oer long-term solutions for emerging microbial resistance to existing
agents and prevention of resistance to new drugs. Perhaps what is
needed is a paradigm shi, a fundamental alteration of the way we use
antibiotics to treat infectious diseases. In this regard, there are lessons
to be learned from plants. For example, plants produce a number of
antimicrobial compounds including a large number of essential oils.
ese essential oils are comprised of numerous compounds which
vary in potency and spectrum of activity both individually and as
mixtures. Plants need this diversity considering the variability in
microbial threats encountered in the environment. us, essential oils
oen inhibit a wide range of microbes due to the synergy aorded by
individual components against multiple bacterial targets. Likewise,
synergy has been documented between existing antibiotics with
specic combinations utilized heavily in current medical practice (e.g.
trimethoprim/sulfamethoxazole; amoxicillin/clavulanate; piperacillin/
tazobactam) [55]. However, synergy between existing antibiotics and
essential oils and/or components has not been thoroughly investigated;
although to date, limited studies have been conducted [56]. For
example, β-lactam antibiotics inhibit cell wall synthesis through
interaction with penicillin-binding proteins (PBP’s) [57]. PBP2a, is a
specic PBP in S. aureus with reduced anity for β-lactam antibiotics
resulting in resistance to these drugs [58]. Interestingly, when β-lactam
antibiotics were combined in vitro with corilagin, a polyphenol derived
from Arctostaphylos uva-ursi, the PBP2a-mediated resistance in MRSA
was overcome with a concomitant reduction in MIC [59]. e authors
postulated that corilagin may interfere with binding of β-lactams to the
PBP2a enzyme resulting in reversion of resistance [60]. Other plant
derived compounds from green tea demonstrated a similar eect in
a dose-dependent manner suggesting the presence of a specic target
[61]. Synergy has also been documented with linalool and α-terpineol
from Melaleuca leucodendron when combined with ampicillin and
kanamycin [62]. In addition, synergy was seen with totarol, ferulenol,
and plumbagin in combination with isoniazid (INH) and rifampin
(RIF) against Mycobacterium tuberculosis (MTB). ese combinations
increased the potency of INH 4-fold against MTB [62]. Another
compound isolated from the roots of Euclea natalensis decreased the
MIC 4- to 6-fold for INH and RIF, respectively [63]. Taken together,
these are important ndings due to the rapid emergence of multidrug-
resistant tuberculosis (MDR-TB) and extensively drug-resistant
tuberculosis (XDR-TB). MDR-TB is dened as resistance to INH
and RIF; XDR-TB is dened as resistance to INH, RIF, and any of the
uoroquinolones and one of the injectable second-line drugs (e.g.
capreomycin, amikacin, or kanamycin) [64,65]. Unfortunately, these
drug-resistant patterns in MTB may become “obsolete” in the near
future, as MTB strains with alarming and more extensive resistance
patterns have been isolated from multiple locations on the globe. ese
strains exhibited resistance to nearly all drugs ever used for treatment
of tuberculosis and other mycobacterial infections including: INH,
RIF, ethambutol, pyrazinamide, ooxacin, moxioxacin, capreomycin,
kanamycin, amikacin, para-aminosalicylic acid, ethionamide,
cycloserine, rifabutin, clofazimine, dapsone, clarithromycin, and
thiacetazone [64]. Although consensus is lacking for a specic acronym
for describing these strains (extremely- versus totally-drug-resistant
TB; XXDR and TDR, respectively), the fact that they have been isolated
is cause for great concern. In the absence of new antibiotics becoming
quickly available for treatment, an alternative approach may be to
combine existing drugs with essential oils. Yet, viable combinations will
require a signicant investment to better understand the mechanism
of action of essential oils and components, determine individual and
combined toxicity, characterize metabolism in vivo, as well as dene
their selectivity and bioavailability.
Summary
Since antiquity, essential oils and their constituents have been

Citation: Boire NA, Riedel S, Parrish NM (2013) Essential Oils and Future Antibiotics: New Weapons against Emerging ‘Superbugs’? J Anc Dis Prev
Rem 1: 105. doi:10.4172/jadpr.1000105
Page 4 of 5
Volume 1 • Issue 2 • 1000105
J Anc Dis Prev Rem
ISSN:JADPR an open access journal
used to treat a large number of human illnesses. Today, essential oils
are used in alternative and holistic medicine for similar purposes and
administered orally, topically or via aromatherapy. A growing number
of scientic investigators have begun the process of elucidating the
specic mechanism(s) of action of essential oils and components.
Emerging evidence has shown that many essential oils have both non-
specic and specic mechanisms of action which varies based on the
relative abundance and chemical composition of the components.
Elucidation of the mechanism of action of these compounds may
enable identication of new antibiotic targets and exploitation of novel
biochemical pathways; pathways not currently targeted by existing
antibiotics. Additionally, combination of existing drugs with essential
oils and/or components may provide an alternative approach to combat
emerging drug resistance. Since antibiotic resistance is currently
outpacing research and development to nd new drugs, humanity is
facing a return to the ‘pre-antibiotic era’. Perhaps the remedies of the
past combined with scientic study may provide the antibiotics of
tomorrow.
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Citation: Boire NA, Riedel S, Parrish NM (2013) Essential Oils and Future Antibiotics: New Weapons against Emerging ‘Superbugs’? J Anc Dis Prev
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Citation: Boire NA, Riedel S, Parrish NM (2013) Essential Oils and Future
Antibiotics: New Weapons against Emerging ‘Superbugs’? J Anc Dis Prev
Rem 1: 105. doi:10.4172/jadpr.1000105
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