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Journal of Medicinal Plants Research Vol. 3(13), pp. 1147-1152, December, 2009
Available online at http://www.academicjournals.org/JMPR
ISSN 1996-0875 © 2009 Academic Journals
Review
Use of bioactive plant products in combination with
standard antibiotics: Implications in antimicrobial
chemotherapy
O. A. Aiyegoro and A. I. Okoh*
Applied and Environmental Microbiology Research Group (AEMREG), Department of Biochemistry and Microbiology,
University of Fort Hare, Private Bag X1314, Alice 5700, South Africa.
Accepted 23 October, 2009
Nowadays, multiple antibiotic resistance by disease-causing microorganisms are a major public health
problem. Antimicrobial compounds from plants have been found to be synergistic enhancers in that
though they may not possess any antimicrobial properties alone, but when used concurrently with
standard drugs they enhance the activity of the drug. The synergistic effect of the association of antibiotic
and plant extracts against resistant pathogens leads to new choices for the treatment of infectious
diseases. Also synergy between bioactive plant product and antibiotics will confront problems of toxicity
and overdose since lesser concentrations of two agents in combination are required, due to these
reasons, there is need therefore, for continuous exploration of multidrug resistance modulating principles
from plants sources.
Key words: Medicinal plants, infectious diseases, synergism, resistance, antimicrobial, chemotherapy.
INTRODUCTION
The plant kingdom has served as an inexhaustible source
of useful drugs, foods, additives, flavouring agents,
lubricants, colouring agents and gums from time
immemorial (Parikh et al., 2005). The therapeutic power
of herbs had been recognized since creation of the
universe and botanic medicine is one of the oldest
practiced professions by mankind (Kambizi and Afolayan,
2001). Medicinal plants have been found useful as
antimalaria, antisickling, anti-helminthic, anti-microbial,
anti-convultant, anti-hypertensive and anti-schistosomal
(molluscicidal) agents (Prescott et al., 2002). The
medicinal actions of plants are unique to particular plant
species or groups, consistent with the concept that the
combination of secondary products in a particular plant is
taxonomically discrete (Parikh et al., 2005). Hugo and
Russell (2003) asserted that 80% of the populations in
developing countries use medicinal plants and as a result
of the importance of herbs in the lives of people, the
World Health Organization devoted 27 centers, out of 915
*Corresponding author. E-mail: aokoh@ufh.ac.za. Tel:
+27406022365, +27822249760. Fax: 0866286824.
collaborating centers worldwide, for traditional medicine
(WHO 2001).
The clinically useful antibiotics now in use have major
setbacks. Apart from the narrow spectrum of anti-
microbial activity many of them have been found to be
neurotoxic, nephrotoxic, ototoxic or hypertensive and few
others cause severe damage to the liver and cause bone-
marrow depression (Chong and Pagano, 1997) and
importantly; infectious pathogens have developed
resistance to all known antibiotics.
Betoni et al. (2006) demonstrated that plants either
contain antimicrobials that can operate in synergy with
antibiotics or posses compounds that have no intrinsic
antibacterial activity but are able to sensitize the
pathogen to a previously ineffective antibiotic. Synergism
is a positive interaction created when two agents
combined and exert an inhibitory effect that is greater
than the sum of their individual effects. Combination
therapy can be used to expand the antimicrobial spec-
trum, to prevent the emergence of resistant mutants, to
minimize toxicity and to obtain synergistic antimicrobial
activity, it could be an alternative to monotherapy for
patients with invasive infections that are difficult to treat,
such as those due to multi-resistant species and for those
1148 J. Med. Plant. Res.
who fail to respond to standard treatment (Kamatou et al.,
2006). Antimicrobial compounds used in combination
might promote the effectiveness of each agent, with
efficacy being achieved using a lower dose of each drug.
Pharmacological benefits would accrue, with one drug
clearing infection from one body system while the other
clears it from a different site (Williamson, 2001). In
addition, synergism in antimicrobials could be utilized in
an attempt to prevent or delay the emergence in vivo of
resistant populations of the pathogenic organisms
(Lupetti et al., 2002).
Abundant medicinal plants have been used in many
forms over the years to treat, manage or control man’s
ailments (Prescott et al., 2002), therefore any effort to
further explore the medicinal or natural products from
man’s botanical flora towards improving health care
delivery deserves attention. This article presents an
overview of the use of bioactive plant products in
combination with standard antibiotics and its implications
in antimicrobial chemotherapy.
HIGHLIGHTS ON SOME ANTIMICROBIAL
PHYTOCHEMICALS
The “phyto” of the word phytochemicals is derived from
the Greek word phyto, which means plant. Therefore,
phytochemicals are defined as bioactive nonessential
plant compounds in fruits, vegetables, grains and other
plant foods that have been linked to reducing the risk of
major chronic diseases. However, more and more
convincing evidences suggest that the benefits of
phytochemicals in plants may be even greater than is
currently understood (Ames and Gold, 1991). Phytoche-
micals can be grouped as carotenoids, phenolics,
alkaloids, nitrogen-containing compounds and organosul-
fur compounds. The most investigated phytochemicals
are the phenolics and carotenoids (Ames and Gold,
1991).
Plants have an almost infinite ability to produce aromatic
substances, most of which are phenols or their oxygen-
substituted derivatives (Kambizi and Afolayan, 2001).
Most are secondary metabolites, of which at least 12,000
have been isolated, a number projected to be less than
10% of the total (Van Wyk et al., 1997). In many cases,
these substances serve as plant defense mechanisms
against predation by microorganisms, insects and
herbivores. Some of the compounds like, terpenoids- give
plants their odors and, quinones and tannins are
responsible for its pigmentations. Many compounds are
responsible for plant flavor (e.g., the terpenoid capsaicin
from chili peppers) and some of the same herbs and
spices used by humans to season food yield useful
medicinal compounds (Pecere et al., 2000). The
isoquinoline alkaloid emetine from the underground part
of Cephaelis ipecacuanha- has been used for many
years as an amoebicidal drug as well as for the treatment
of abscesses due to the spread of Entamoeba histolytica
infections (Iwu et al., 1999).
Another important compound of plant origin with a long
history of use is quinine- an alkaloid which occurs
naturally in the bark of Cinchona trees. Apart from its
continued usefulness in the treatment of malaria, it can
also be used to relieve nocturnal leg cramps (Iwu et al.,
1999). Similarly plants have made important contributions
in the areas beyond anti-infective, such as cancer
therapies. Examples include the antileukaemic alkaloids,
vinblatine and vincristine, which were both obtained from
the Madagascan periwinkle (Catharanthus roseus syn.
Vinca roseus) (Nelson, 1982). Other therapeutic com-
pounds from plants include taxol, homoharringtonine and
several derivatives of camptothein, which are all anti-
cancer. A well known benzylisoquinoline alkaloid,
papaverine, has been shown to have a potent inhibitory
effect on the replication of several viruses including
cytomegalovirus, measles and Human Immunodeficient
Virus (HIV) (Turano et al., 1989).
Atropisomeric naphthyl isoquinoline alkaloid dimmers,
michellamines A, B and C were isolated from Ancistro-
cladus korupensis, and the three compounds showed
potential anti-HIV activities. Kambizi and Afolayan (2001)
isolated three compounds from Aloe ferox, a plant
traditionally used for the treatment of sexually transmitted
infections. These compounds includes; 1, 8 – dihydroxy –
3 – hydroxymethyl - 9, 10 - anthracenedione (aloe -
emodin); 1, 8 – dihydroxy – 3 – methyl - 9, 10 -
anthracenedione (chrysophanol), and 10 – C – b – D –
glucopyranosyl - 1, 8 – dihydroxy – 3 –hydroxymethyl - 9
- anthracenone (aloin A), and these three compounds
exhibited antibacterial activities against Bacillus subtilis,
Staphylococcus epidermidis, Shigella sonnei and
Escherichia coli.
Aloe emodin has also been reported to be an anticancer
agent with selective activity against neuroectodermal
tumors (Pecere et al., 2000) and generally, both aloe-
emodin and aloin A have been associated with other
biological and medicinal activities that include laxative
action (Van Wyk et al., 1997). Mangena and Muyima
(1999) reported antimicrobial activities of essential oils in
Artemisia afra, Pteronia incana and Rosmarinus
officinalis. All these plants have been used in the
treatment of common cold, diabetes mellitus, bronchial
complaints and stomach disorder. The essential oils from
these plants were reported to contain such components
as Bornylacetate, Camphene, Camphor, 1-8-Cineole, o-
Cymene, p-Cymene, Limonene + 1, 8 Cinole, Mycerene,
-Pinene, -Pinene, -Thujone, -Thujone and Verbone
to mention a few.
Dilika et al. (2000) also reported the antibacterial
activities of linoleic and oleic acids isolated from the dry
leaf of Helichrysum pedunculatum, a plant used to treat
wound acquired during male circumcision rites in the
Eastern Cape of South Africa and this study has been
corroborated by Aiyegoro et al. (2008a). Two lipophilic
Aiyegoro and Okoh 1149
Table 1. Some major classes of antimicrobial compounds from medicinal plants and their mechanisms of actions (Cowan, 1999).
Class Sub-class Example(S) Mechanism
Phenolics
Simple phenols
Catechol Epicatechin Substrate deprivation
Membrane disruption
Phenolics Phenolic acid Cinamic acid Membrane disruption
Phenolics Quinones Hypericin Bind to adhesins, complex with cell wall and
inactivate enzymes.
Phenolics Flavonoids Chrysin Bind to adhesins
Phenolics Flavones Complex with cell wall
Phenolics
Abyssinome Inactivate enzymes, inhibit HIV reverse
transcriptase
Phenolics Tannins Ellagitannins Bind to proteins and adhesins, enzyme inhibitor,
substrate deprivation, complex with cell wall,
membrane disruption, metal ion complexation.
Phenolics Coumarins Warfarin Interaction with eukaryotic DNA (antiviral activity).
Terpenoids, Essential oils Capsaicin Membrane disruption
Alkaloids Berberine, Piperine Intercalate into cell wall and/or DNA.
Lectins and Polypeptide Mannose-specific agglutinin Block viral fusion or adsorption
Lectins and Polypeptide Fabatin Form disulfide bridge
Polyacetylenes
8S-Heptadeca-2(z), 9(z)-
diene-4, 6-diyne-1, 8-diol
Membrane disruption
phytoalexins: -amyrin and -amyrin that have anti-
tuberculosis and generally antibacterial activities have
also been isolated from Helichrysum kraussii (Prinsloo
and Meyer, 2006). Many more compounds with
antibacterial potentials from different species of plants
have been isolated (Park et al., 2008; Tsao and Yin,
2001; Iwu et al., 1999; Smith et al., 2007). It is also
notable that, more novel antibacterial compounds have
been isolated from plants and their structures elucidated
on daily basis but have not been documented in any
pharmacopeia.
Many plant extracts clearly demonstrate antibacterial
properties, although the mechanistic processes are poor-
ly understood. Cowan (1999) describe the mechanism of
action of various classes of active components of
medicinal plants (Table 1).
ANTIMICROBIAL SYNERGISMS IN PLANTS
PRODUCTS
Plants antimicrobials have been found to be synergistic
enhancers in that though they may not have any
antimicrobial properties alone, but when they are taken
concurrently with standard drugs they enhance the effect
of that drug (Kamatou et al., 2006). The synergistic effect
from the association of antibiotic and plant extracts
against resistant bacteria leads to new choices for the
treatment of infectious diseases. This effect enables the
use of the respective antibiotic when it is no longer
effective by itself during therapeutic treatment (Nascimento
et al., 2000). The application of synergistic principle is
evident in commercial preparations for the treatment of
various infections (e.g. the antibiotic Augmentin).
Traditional healers often use combinations of plants to
treat or cure diseases (Kamatou et al., 2006). One
notable example from the ethnobotanical literature is the
concomitant administration of various Salvia species with
Leonotis leonurus to treat various infections (Masika and
Afolayan, 2003).
Kamatou et al. (2006), confirmed the existence of
synergism between Salvia chamelaeagnea and L.
leonurus, when these two plants were combined together
against Bacillus cereus, S. aureus, E. coli and Klebsiella
pneumoniae. They as well reported synergism when the
tincture of L. leonurus and various Salvia species were
combined together against influenza. Boik (2001)
conducted a large number of combination studies using
various natural substances and their results strongly
suggested that when used in combination, natural
substances can produce synergistic effects. It is thought
that phenolic compounds such as flavonoids may
increase the biological activity of other compounds by
synergistic or other mechanisms (Williamson, 2001).
Experimental evidence of synergistic actions between plants
was also shown in a clinical study on the formulation of
Chinese herbs used to treat eczema (Williamson, 2001).
COMBINATIONS OF BIOACTIVE PLANT PRODUCTS
AND DIFFERENT CLASSES OF ANTIBIOTICS WITH
SPECIFIC MECHANISM OF ACTION
In the treatment of drug resistant infections, combinations
of antibiotics have often been used as this takes
advantage of different mechanisms of action. The use of
1150 J. Med. Plant. Res.
antimicrobial agents displaying synergy is one of the well
established indications for combination antimicrobial
therapy (Rybak and McGrath, 1996). Combinations of
antimicrobials that demonstrate an in vitro synergism
against infecting strains are more likely to result in
successful therapeutic result. Thus, evidence of in vitro
synergism could be useful in selecting most favorable
combinations of antimicrobials for the practical therapy of
serious bacterial infections (Hooton et al., 1984).
It has been proven that, in addition to the production of
intrinsic antimicrobial compounds, plants also produce
Multi-Drug Resistance (MDR) inhibitors which enhance
the activity of the antimicrobial compounds (Stermitz et
al., 2000a). Tegos et al. (2002) showed that the activity of
presumed plant antimicrobials against gram positive and
gram negative organisms was significantly enhanced by
synthetic MDR inhibitors of MDR efflux proteins. The
findings provided a basis that plants can be prospective
sources of natural MDR inhibitors that can modulate the
performance of antibiotics against resistant strains.
The screening of crude plant extracts for synergistic
interaction with antibiotics is expected to provide ways for
the isolation of MDR inhibitors. The ability of crude
extracts of plants to potentiate the activity of antibiotics
has been observed by some researchers (Aiyegoro et al.,
2008b, 2009; Sibanda and Okoh, 2008; Betoni et al.,
2006; Darwish et al., 2002; Isogai et al., 2001; Ahmad
and Aqil, 2006), and it is anticipated to form the basis for
the bioassay directed fractionation of potential resistance
modulators from plants. Darwish et al. (2002) carried out
a study on some Jordanian plants and they demonstrated
that the efficacy of the antibiotics, gentamycin and
chloramphenicol against S. aureus were reportedly
improved by the use of plant materials. Ahmad and Aqil
(2006), also reported that crude extracts of Indian
medicinal plants demonstrated synergistic interaction with
tetracycline and ciprofloxacin against extended spectrum
-lactamase (ESL)-producing multidrug-resistant enteric
bacteria. Betoni et al. (2006) also observed synergistic
interactions between extracts of Brazilian medicinal
plants and eight antibiotics on S. aureus. The use of
Catha edulis extracts at subinhibitory levels, has been
reported to reduce the Minimum Inhibitory Concentration
(MIC) values of tetracycline and penicillin G against
resistant oral pathogens, Streptococcus oralis, Streptoco-
ccus sanguis and Fusobacterium nucleatum (Al- hebshi
et al., 2006).
A number of compounds with an in vitro activity of
reducing the MICs of antibiotics against resistant orga-
nisms have also been isolated from plants. Polyphenols
(epicatechin gallate and catechin gallate) have been
reported to reverse beta-lactam resistance in Methicillin
Resistant S. aureus (MRSA) (Stapleton et al., 2004).
Diterpenes, triterpenes, alkyl gallates, flavones and
pyridines have also been reported to have resistance
modulating abilities on various antibiotics against resistant
strains of S. aureus (Marquez et al., 2005; Smith et al.,
2007; Shibata et al., 2005; Oluwatuyi et al., 2004).
The synergies detected in these studies as enume-
rated above were not specific to any group of organisms
or class of antibiotics. This suggests that plant crude
extracts is a blend of compounds that can enhance the
activity of different antibiotics. Plants have been known to
contain myriads of antimicrobial compounds (Iwu et al.,
1999) such as polyphenols and flavonoids. The anti-
microbial and resistance modifying potentials of naturally
occurring flavonoids and polyphenolic compounds have
been reported in other studies such as Cushnie and
Lamb (2005), Sato et al., (2004).
Some of these compounds like polyphenols have been
shown to exercise their antibacterial action through
membrane perturbations. This disruption of the cell
membrane coupled with the action of beta-lactams on the
transpeptidation of the cell membrane could lead to an
enhanced antimicrobial effect of the combination
(Esimone et al., 2006). It has also been revealed that
some plant derived compounds can improve the in vitro
activity of some peptidoglycan inhibiting antibiotics by
directly attacking the same site (that is, peptidoglycan) in
the cell wall (Zhao et al., 2001).
While the above explanations may account for the
synergy between the extracts and beta-lactam antibiotics
that act on the cell wall, it might not apply in the case of
the observed synergy with other classes of antibiotics
with different targets such as tetracyclines, erythromycin,
ciprofloxacin and chloramphenicol. Bacterial efflux pumps
are responsible for a considerable level of resistance to
antibiotics in pathogenic bacteria (Kumar and Schweizer,
2005). Some plant derived compounds have been
observed to augment the activity of antimicrobial
compounds by inhibiting MDR efflux systems in bacteria
(Tegos et al., 2002). 5’-methoxyhydnocarpin is an
example of an inhibitor of the NorA efflux pump of S.
aureus isolated from Berberis fremontii (Stermitz et al.,
2000b). Such compounds are likely to be broad spectrum
efflux inhibitors considering that the synergistic effect of
the extract was observed on both gram positive and gram
negative organisms as well as in combination with, cell
wall inhibiting and protein synthesis inhibiting antibiotics.
Importantly, some broad spectrum efflux pump inhibitors
have been isolated from some plants. Smith et al. (2007)
reported one efflux inhibitor (ferruginol) from the cones of
Chamaecyparis lawso-niana, which inhibited the activity
of the quinolone resistance pump (NorA), the tetracycline
resistance pump, (TetK) and the erythromycin resistance
pump, (MsrA) in S. aureus.
PERSPECTIVES
Traditionally used medicinal plants have received the
attention of the pharmaceutical and scientific commu-
nities. This involves the isolation and identification of the
secondary metabolites produced by the plants and used
as the active principles in medical preparations (Taylor et
al., 2001). Historically, many plant oils and extracts, such
as tea tree, myrrh and clove, have been used as topical
antiseptics, or have been reported to have antimicrobial
properties. It is important to scientifically investigate those
plants which have been used in traditional medicines as
potential sources of novel antimicrobial compounds. Also
the resurgence of interest in natural therapies and
increasing consumer demand for effective, safe, natural
products means that quantitative data on plant oils and
extracts are required.
The primary benefits of using plant derived medicines
are that they are relatively safer than synthetic
alternatives, offering profound therapeutic benefits and
more affordable treatment (Van Wyk and Gericke, 2000).
Plants based antimicrobials represent a vast untapped
source for medicine. Continued and further exploration of
plant antimicrobials needs to occur because plant based
antimicrobials have enormous therapeutic potentials.
They are effective in the treatment of infectious diseases
while simultaneously mitigating many of the side effects
that are often associated with synthetic drugs. Various
reports have documented the enhanced antimicrobial
activities (that is, synergistic potentials) of standard
antibiotics in combinations with plant extracts even when
the organisms are no more susceptible to the drug.
Synergistic interactions are of vital importance in
phytomedicine, to explain the efficacy of apparently low
doses of active constituents in an herbal product. This
concept, that a whole or partially purified extract of a
plant offers advantages over a single isolated ingredient,
also underpins the philosophy of herbal medicine. Both
literature reports and ethnobotanical records indicate a
general consensus on the use of antimicrobially active
medicinal plants to provide cheaper drugs that may
complement existing supplies from orthodox medicine in
the Primary Health programme and/or provide novel or
lead compound that may be employed in controlling
infections in our communities (Betoni et al., 2006).
Conclusion
With the relative absence of new antimicrobials coming to
market and with the new threats arising from the
microorganisms, the number of drug options leaves us
perilously close to none or only a single effective agent
for some life-threatening infections. Plants, the sleeping
giants of pharmaceutical industry, are an inexhaustible
source of natural drugs that may be employed in
combating ailments and inconveniences resulting from
microbial attacks. Assessing the therapeutic potentials of
plants from the traditional African system of medicine
could insight us as to how best these plants can be used
in the treatment of diseases, especially, when the syner-
gistic prowess between plants and standard antibiotics is
optimally resourced. An important aspect of the research
focus of our laboratory involves definite studies of the
antimicrobial synergistic potentials of South African
medicinal plants. The search for more natural antimicro-
Aiyegoro and Okoh 1151
bial substances is an ongoing exercise.
ACKNOWLEDGEMENT
We thank the National Research Foundation of South
Africa for financial support.
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