Download Combination therapy: Synergism between natural plant extracts and

Science against microbial pathogens: communicating current research and technological advances
______________________________________________________________________________
A. Méndez-Vilas (Ed.)
Combination therapy: Synergism between natural plant extracts and
antibiotics against infectious diseases
Sumitra Chanda* and Kalpna Rakholiya
Phytochemical, Pharmacological and Microbiological Laboratory, Department of Biosciences, Saurashtra University,
Rajkot 360 005, Gujarat, India
* Author for correspondence, E-mail: [email protected]
Antibiotics are one of the most important weapons in fighting bacterial infections and have greatly benefited the
health‐related quality of human life since their introduction. However, over the past few decades these health benefits are
under threat as many commonly used antibiotics have become less and less effective against certain illnesses not only
because many of them produce toxic reactions but also due to emergence of drug resistant bacteria. Resistance
development is an even bigger problem since the bacterial resistance is often not restricted to the specific antibiotic
prescribed, but generally extends to other compounds of the same class. Bacterial resistance and its rapid increase is a
major concern of global public health and is emerging as one of the most significant challenges to human health. Treating
bacterial infections by antibiotics is beneficial but their indiscriminate use has led to an alarming resistance among
microorganisms as well as led to re-emergence of old infectious diseases. One approach to treat infectious diseases is the
use of plant extracts individually and /or as an alternative approach is the use of combination of antibiotics with plant
extracts. This latter approach i.e. combination therapy or synergistic therapy; against resistant microorganisms may lead to
new ways of treating infectious diseases and probably this represents a potential area for further future investigations.
Combination therapy is helpful and useful for patients with serious infections caused by drug resistant pathogens. The
present review describes in detail, the observed synergy between natural extracts and standard antibiotics combating
bacterial and fungal infections. The mode of action of combination therapy significantly differs from that of the same
drugs acting individually; therefore the selection of an appropriate combination is crucial and essential which requires
understanding the potential interaction between the plant extracts and antimicrobial agents.
Keywords Synergistic therapy; antimicrobics; natural extracts; multidrug resistance; standard antibiotics
1. Introduction
Infectious diseases caused by bacteria and fungi affect millions of people worldwide. Throughout the history of
mankind, infectious diseases have remained a major cause of death and disability. Today, infectious diseases account
for one-third of all deaths in the world; the World Health Organization estimates that nearly 50,000 people die each day
throughout the world from infectious diseases. The discovery of antibiotics was an essential part in combating bacterial
infections that once ravaged humankind. Different antibiotics exercise their inhibitory activity on different pathogenic
organisms. The development and spread of resistance to currently available antibiotics is a worldwide concern.
The increasing phenomenon of acquisition of resistance among microorganisms to antimicrobial drugs is attributed to
the indiscriminate and improper use of current antimicrobial drugs [1]. Today, clinically important bacteria are
characterized not only by single drug resistance, but also by multiple antibiotic resistance - the legacy of past decades of
antimicrobial use and misuse [2]. Drug resistance presents an ever increasing global health threat that involves all major
microbial pathogens and antimicrobial drugs [3, 4]. These are difficult to treat and are responsible for a variety of
infectious diseases. For over a decade, the pace of development of new antimicrobial agents has slowed down while the
prevalence of resistance has grown at an astronomical rate. The rate of emergence of antibiotic resistant bacteria is not
matched by the rate of development of new antibiotics to combat them [5].
Antibiotics that work today may not work tomorrow. It is essential to investigate newer drugs to which there is lesser
resistance [6]. As resistance to old antibiotics spreads, the development of new antimicrobial agents has to be expedited
if the problem is to be contained. However, the past record of rapid, widespread emergence of resistance to newly
introduced antimicrobial agents indicates that even new families of antimicrobial agents will have a short life
expectancy [7].
The steadily increasing bacterial resistance to existing drugs is a serious problem, and therefore there is a dire need to
search for new classes of antibacterial substances, especially from natural sources. Unlike synthetic drugs,
antimicrobials of plant origin are not associated with side effects and have a great therapeutic potential to heal many
infectious diseases [8, 9]. Sometimes the use of single antibiotic does not produce the desired effective inhibitory effects
and to overcome this, a combination of drugs often exercises their synergistic effect which surpasses their individual
performance. The synergistic effect may be due to certain complex formation which becomes more effective in the
inhibition of a particular species of microorganisms either by inhibiting the cell wall synthesis or by causing its lyses or
death.
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A. Méndez-Vilas (Ed.)
2. First approach to meet the threat of resistant microorganisms
The increasing development of drug resistance in human pathogens is cause for concern, because of the number of
patients in hospitals who have suppressed immunity, and due to new bacterial strains, which are multi drug resistant
(Fig. 1). Consequently, new infections can occur in hospitals resulting in high mortality. The problem of microbial
resistance is growing and the outlook for the use of antimicrobial drugs in the future is still uncertain. The first approach
to meet this situation was the development of antibiotics.
Fig. 1 Microorganisms resistance to multiple antibiotics.
Antibiotics are traditionally defined as natural compounds, produced by microorganisms, with selective antibacterial
activity that does not have any strong side effects on human. Their mechanism of action is either through killing the
bacteria (bactericidal effect) or by inhibiting bacterial growth (bacteriostatic effect). The discovery of antibiotics had
eradicated the infections that once ravaged humankind. But their indiscriminate use has led to the development of
multidrug-resistant pathogens. Around 90–95% of Staphylococcus aureus strains worldwide are resistant to penicillin
[10] and in most of the Asian countries 70–80% of the same strains are methicillin resistant [11]. The introduction of
penicillin paved the way for the exploration of various natural compounds, with different targets in the bacterial cell.
Penicillin attacks bacteria by inhibiting the cell wall biosynthesis, making the cell wall a weak spot and causing cell
lysis. Other substances target different sites within the bacteria and have different effects including inhibition of DNA
replication, RNA synthesis and protein synthesis (Fig. 2).
Therefore, actions must be taken to reduce this problem, for example, to control the use of antibiotic, develop
research to better understand the genetic mechanisms of resistance, and to continue studies to develop new drugs, either
synthetic or natural. The ultimate goal is to offer appropriate and efficient antimicrobial drugs to the patient.
Fig. 2 Bacterial targets of current antibiotics used in the clinic.
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Science against microbial pathogens: communicating current research and technological advances
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A. Méndez-Vilas (Ed.)
3. Second approach to meet the threat of resistant bacteria
An alternative therapy to treat antibiotic resistant microorganisms is the use of plant extracts. Drugs derived from
natural sources play a significant role in the prevention and treatment of human diseases. There are several reports on
the antimicrobial activity of different plant extracts that were effective antimicrobics [12-16]. Several plant extracts
exhibited synergistic activity against a large panel of microorganisms (Table 1). There are many advantages of using
antimicrobial compounds from medicinal plants, such as fewer side effects, better patient tolerance, less expensive,
acceptance due to long history of use, and being renewable in nature [17] and also higher plants represent a potential
source of novel antibiotic prototypes [18]. However, the problem of drug resistance is on the increase. The need of the
hour is to develop still newer, useful and important antimicrobial agents [19, 20]; or new ways to treat the resistant
microorganisms. An alternative approach is the use of combination therapy i.e. synergism between known antimicrobial
agents (antibiotics) and bioactive plant extracts. This is a novel concept which has been recently ventured.
4. Third approach to meet the threat of resistant bacteria
As high level acquired resistance to conventional antibiotics is frequent, it is reasonable to use combination therapy in
order to achieve bactericidal synergism. One strategy employed to overcome these resistance mechanisms is the use of
combination therapy. The combination can be of different plant extracts or plant extracts with standard antibiotics or
antibiotics with some chemicals. Such combinations i.e. association of antibiotics with plant extracts against resistant
bacteria will have different mechanisms of action and it may lead to new choices for the treatment of infectious
diseases.
Combination therapy can be used to expand the antimicrobial spectrum, to prevent the emergence of resistant
mutants, to minimize toxicity, thereby exhibiting antimicrobial activity greater than that would be expected from each
antimicrobial drug individually. Synergy is often associated with the cliche “the whole is greater than the sum of the
parts”, an idea which emerged at the time of Aristotle (350 AC), and is described in his work Metaphysics. But synergy
is not always greater than the sum of the parts, in some cases; the synergic result is merely different. Synergism is
defined as a positive interaction created when two agents are combined and together they exert an inhibitory effect (on
the targeted organisms) that is greater than the sum of their individual effects. Antagonism occurs when the effect of
two drugs together is less than the effect of either alone and indifference when no effect is exhibited. In rational drug
therapy, the concurrent administration of two or more drugs is often essential and sometimes mandatory in order to
achieve the desired therapeutic goal or to treat co-existing diseases. However, the drug interactions may have different
effects on the host as well as the infecting microorganisms. The potential benefits of using combined antimicrobial
therapy can be treatment of mixed infections, therapy of severe infections in which a specific causative organism is
known, enhancement of antibacterial activity, reducing the time needed for long-term antimicrobial therapy and
prevention of the emergence of resistant microorganisms [21].
5. Review of reported synergistic activity of some plant extracts and antibiotics
In phytotherapy, there are potentially significant advantages associated with the synergistic interactions which may be
of different antibiotics, or plant extracts or the synergy may be of antibiotic and plant extract. The advantages are (1)
increased efficiency (2) reduction of undesirable effects (3) increase in stability or bioavailability of the free agents and
(4) obtaining an adequate therapeutic effect with relatively small doses, when compared with a synthetic medication
[22]. Plant 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 [23]. Drug synergism between known antimicrobial agents and bioactive plant extracts is a new concept; a few
examples are described below and the summary is given in Table 2.
Souto de Oliveira et al. [24] investigated the synergistic activity of norfloxacin, tetracycline and erythromycin with
ethanol extract of Mangifera indica L. peel against S. aureus strains. Individual extract did not display significant
antibacterial activity (MIC ≥ 2048 μg/ml), but it modulated the activity of antibiotics (MIC = 512 μg/ml), i.e. in
combination with antibiotics, a four-fold reduction in the MIC values for tetracycline and erythromycin was observed.
The study indicated that mango peel could serve as a source of potential adjuvant of antibiotics, which adds value to this
mango by-product.
Toroglu [25] investigated in-vitro synergistic effects of different spices and herbs (Rosmarinus officinalis,
Coriandrum sativum, Micromeria fruticosa L., Cumium cyminum, Mentha piperita) with gentamicin, cephalothin,
ceftriaxone and nystatin against 13 microbial species. This study suggested that essential oils of tested spices and herbs
could protect some bacterial strains and the combination of plant extract with antibiotics further reduced drug
resistance. The synergistic effects obtained could lead to new choices for the treatment of infectious diseases.
Adikwu et al. [26] investigated the in vitro combined effects of erythromycin and methanol extract of leaves of
Euphorbia hirta against clinical isolates of Staphylococcus aureus using the Checkerboard technique. The organism
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was susceptible to the extract with MIC of 25 mg/ml, while erythromycin had MIC of 0.005 mg/ml. Synergistic effect
was obtained by a combination of erythromycin and E. hirta against S. aureus in the ratios (9:1, 8:2, 7:3, 6:4, 3:7, 2:8,
1:9) while others (5:5, 4:6) showed indifference. Combined drug use is recommended to prevent resistance emerging
during treatment and to achieve higher efficacy in the treatment of infections and other diseases.
Adwan et al. [27] investigated in vitro interaction between ethanolic extracts of Rhus coriaria (seed), Sacropoterium
spinosum (seed), Rosa damascene (flower) and certain known antimicrobial drugs including oxytetracycline HCl,
penicillin G, cephalexin, sulfadimethoxine as sodium and enrofloxacin. Synergy testing of these extracts and antibiotics
was carried out against 3 multidrug-resistant Pseudomonas aeruginosa strains. The synergy between R. coriaria and
antibiotics showed a high decrease in MIC and a strong bactericidal activity. These results indicated that combination
between R. coriaria extract and antibiotics could be useful in fighting emerging drug-resistant P. aeruginosa.
Purushotham et al. [28] investigated synergistic activity of tetracycline with methanolic extract of Tectona grandis
against 9 different Gram-positive and Gram negative bacteria. The MIC values were less with tetracycline alone (>500
μg/ml) and it was still lesser with methanolic extract of T. grandis. However, MIC was least with combination of
tetracycline and methonolic extract of T. grandis (62.5 μg/ml) against Psedomonas aeruginosa and Serratia
marcescens.
Stanojevic et al. [29] investigated in vitro synergistic antibacterial activity of aqueous extract of Salvia officinalis L.
and its synergistic action with the preservatives sodium nitrite, sodium benzoate and potassium sorbate against selected
food spoiling bacteria. Synergism was assessed by the Checkerboard assay method and quantitatively represented by
the FIC index. The combination of the aqueous extracts with sodium nitrite, sodium benzoate, potassium sorbate
inhibited the growth of a significant number of bacterial species at a lower concentration than when single agents were
assayed separately. The MIC values of the aqueous extract were reduced up to ¼ MIC and the MIC of sodium nitrite up
to 1/8 MIC values.
Adwan et al. [30] evaluated the possible In vitro interaction between ethanolic extracts of Rus coriaria (seed),
Sacropoterium spinosum (seed) and Rosa damascena (flower) and certain known antimicrobial drugs including
oxytetracycline HCl, penicillin G, cephalexin, sulfadimethoxine as sodium and enrofloxacin against clinical isolates of
methicillin-resistant Staphylococcus aureus. In this study, competitive inhibitor and protein synthesis inhibitors showed
high synergism rate with plant extracts, while nucleic acid synthesis inhibitor did not show this effect.
Ahmed et al. [31] investigated inhibitory effect of two antibiotics viz., penicillin and tetracycline against
Staphylococcus aureus individually and in combination with ethanol extract of leaf and stem of Salvadora persica. The
highest synergistic effect was observed when S. aureus was exposed to tetracycline with stem extract of S. persica. It
was followed by tetracycline with leaf extract of S. persica. The combination of stem and leaf extract with penicillin did
not produce the same inhibitory effect as that of tetracycline and S. persica stem and leaf extracts. In order to control a
particular disease, in vitro experiment should be carried out with various antibiotics and their combination as well as
antibiotics and plant extracts. Therefore, a right combination may be administered to the patient for early and safe
recovery from a specific ailment.
Aiyegoro et al. [32] investigated acetone, chloroform, ethyl acetate and methanol extract of Helichrysum longifolium
in combination with six antibiotics comprising of penicillin G sodium, amoxicillin, chloramphenicol, oxytetracycline,
erythromycin and ciprofloxacin using both the time-kill and the Chekerboard methods against a panel of bacterial
isolates comprised of referenced, clinical and environmental strains. In time-kill method, Synergistic response was
about 65%, indifference 28.33% and antagonism was 6.67%. In checkerboard method, 61.67% of all the interactions
were synergistic, while indifference interactions were 26.67% and antagonistic interactions were approximately
11.66%. The Checkerboard method revealed that the extracts improved bactericidal effects of the antibiotics.
Chatterjee et al. [33] investigated in vitro synergistic effect of doxycycline and ofloxacin in combination with
ethanolic leaf extract of Vangueria spinosa against four pathogenic bacteria. The MIC/MBC values for ethanolic leaf
extract of V. spinosa against all the tested bacteria ranged between 25.5 - 52.6/22.4 - 60.5 μg/ml, for doxycycline
4.0/4.0 - 4.5 μg/ml and for ofloxacin 0.625 - 2.5/1.25 - 5.0 μg/ml respectively. Synergistic actions were observed in all
the cases except against P. aeruginosa which showed an additive effect for ofloxacin and plant extract combination.
Data from the literature as well as this result revealed the potential of plants in therapeutic treatment.
Saravana Kumar et al. [34] investigated the synergistic activity of oxytetracycline with methanolic extract of
Thespesia populnea. MIC of methanolic extract in combination with oxytetracycline using 12 different Gram positive
and Gram negative bacteria was found to be around (62.5 μg/ml to 1000 μg/ml). The MIC of methanolic extracts of T.
populnea in combination with oxytetracycline was found to be less. The highest synergistic activity was found against
Shigella boydii (36 mm, zone of inhibition Diameter).
Odunbaku et al. [35] reported synergistic activity between standard antibiotics and ethanolic extract of Ficus
exasperata leaf on Escherichia coli and Staphylococcus albus. In this study, antibiotics were selected in such a way that
the different antibiotics have different targets on bacteria (protein synthesis, nucleic acid, cell wall synthesis). The MIC
of the plant extract against E. coli was 300 mg/ml while that of S. albus was 700 mg/ml. The study revealed that the
combination of the crude plant extract and the protein synthesis inhibitors had the highest inhibitory activity.
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Leaves
Leaves
Leaves
Aerial part
Diospyros ebenum Roxb.
(Ebenaceae)
Eucalyptus citriodora Hk
(Myrtaceae)
Hyptis martiusii Benth.
(Labiatae)
Leaves
Aerial part
Part used
Coccinia grandis L.
(Cucurbitaceae)
Cinnamomum iners Schaeff.
(Lauraceae)
Andrographis paniculata
(Burm.f.) Wall.
(Acanthaceae)
Plant Name
(Family)
©FORMATEX 2011
ET (95%)
DO, ME, AC, ET, AQ
PE, EA, ME, AQ
ET, AQ
ME
CH, CH + HCl (1M)
Extract
Escherichia coli
Pseudomonas pseudoalcaligenes, Proteus vulgaris, Citrobacter freundii,
Staphylococcus subflava, Bacillus megaterium, Enterobacter aerogenes
Bacillus subtilis, Staphylococcus aureus, Pseudomonas aeruginosa,
Salmonella typhimurium, Enterobacter aerogenes
Candida albicans, Aspergillus niger, Bacillus subtilis, Bacillus pumilus,
Enterococcus faecalis, Bacillus licheniformis, Staphylococcus aureus,
Streptococcus faecalis, Shigella boydii-Type12, Shigella flexneri9, Shigella
dysenteriae-3 , Pseudomonas aeruginosa , Escherichia coli, Salmonella typhi-62 ,
Salmonella choleraesuis-36 , Shigella boydii-8, Shigella flexneri NICED, Shigella
sonnei
Staphylococcus aureus
Staphylococcus aureus, Bacillus subtilis, Enterobacter faecalis, Staphylococcus
epidermidis, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae,
Salmonella typhimurium, Enterobacter cloacae
Microorganisms
Table 1 List of some plant extracts showing antimicrobial activity against a panel of microorganisms causing infectious diseases.
[40]
[12]
[39]
[38]
[37]
[36]
Reference
Science against microbial pathogens: communicating current research and technological advances
______________________________________________________________________________
A. Méndez-Vilas (Ed.)
©FORMATEX 2011
Cones
Root
Leaves
Metasequoia glyptostroboides
Miki ex Hu
(Cupressaceae)
Piper ribesoides Wall
(Piperaceae)
Polyalthia longifolia (Sonn.) Thw.
var. Pendula
(Annonaceae)
PE, ME, AC, DO,
DMF
ME, AC, DO
ME
EA
PE, ME, AQ
PE, CH, EA, AC, ME
[46]
[45]
Staphylococcus sp.-13, S. aureus, S. epidermidis, S. subfava, Bacillus cereus, B.
subtilis, B. megaterium, M. flavus, Pseudomonas sp.-16, P. aeruginosa, P.
testosterone, P. pseudoalcaligenes, E. coli-15, E. coli, Enterobacter sp.-2, E.
aerogenes, Klebsiella sp.-5, K. pneumoniae, Proteus sp.-2, P. mirabilis, P.
vulgaris, P. morganii, Providencia sp.-1, Citrobactor sp.-2, C. freundii,
Alcaligenes fecalis, Salmonella typhimurium, Candida sp.-5, C. albicans-2, C.
glabrata, C. tropicalis, C. apicola, Cryptococcus neoformans, C. luteolus,
Trichosporan beigelii, Aspergillus flavus, A. candidus A. niger
Staphylococcus epidermidis, Enterobacter aerogenes, Bacillus megaterium,
Proteus morganii, Alcaligenes fecalis
[44]
[43]
[42]
Staphylococcus aureus
Listeria monocytogenes, Salmonella typhimurium, Salmonella enteritidis,
Escherichia coli, Enterobacter aerogenes, Staphylococcus aureus
Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas
aeruginosa
[41]
ET: Ethanol; AQ: Aqueous; AC: Acetone; CH: Chloroform; EA: Ethyl acetate; ME: Methanol; HCL: Hydrochloric acid; PE: Petroleum ether; DO: 1,4-dioxan; DMF: N,N-dimethylformamide
Seed, aerial
part
Leaves
Merremia emarginata Hallier f.
(convolvulaceae)
Psoralea corylifolia L.
(Fabaceae)
Seed
Mangifera indica L.
(Anacardiaceae)
Staphylococcus aureus, Staphylococcus epidermidis, Bacillus subtilis,
Micrococcus flavus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella
pneumoniae, Proteus vulgaris, Proteus mirabilis, Citrobacter freundii,
Salmonella typhimurium, Candida albicans, Candida tropicalis, Cryptococcus
luteolus
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Rhus coriaria L.
(Anacardiaceae), Psidium
guajava L. (Myrtaceae),
Lawsonia inermis L.
(Lythraceae),
Sacropoterium spinosum L.
(Rosaceae)
Rhus coriaria L.
(Anacardiaceae),
Sacropoterium spinosum L.
(Rosaceae), Rosa
damascene Mill.
(Rosaceae)
ET
Mangifera indica L.
(Anacardiaceae)
Staphylococcus aureus
Pseudomonas aeruginosa
Oxytetracyclin
HCl,
enrofloxacin,
gentamicin sulphate, sulphadimethoxin
Oxytetracycline HCl, penicillin G, cephalexin,
sulfadimethoxine as sodium, enrofloxacin
ET
Staphylococcus aureus
ET
Norfloxacin, tetracycline, erythromycin
Pseudomonas aeruginosa ATCC19582, Staphylococcus aureus
ATCC6538, Bacillus cereus ATCC10702, Bacillus pumilus
ATCC14884, Proteus vulgaris ATCC6830, Acinetobacter calcaoceticus
anitratus CSIR, Staphylococcus aureus OKOH1, Shigella flexineri,
Salmonella spp., Micrococcus kristinae
Penicillin
G
sodium,
chloramphenicol,
oxytetracycline, erythromycin
AC,
CH,
EA,
ME,
AQ
Helichrysum longifolium
DC.
(Asteraceae)
amoxicillin,
ciprofloxacin
Escherichia coli, Staphylococcus albus
Gentamicin,
tetracycline,
ampicillin,
chloramphenicol,
erythromycin,
samtrim,
pro.penicillin
ET
Ficus exasperata Vahl
(Moraceae)
Microorganisms
Staphylococcus aureus
Antibiotics
Erythromycin
ME
Extract
Euphorbia hirta L.
(Euphorbiaceae)
Plant name
Table 2 Synergistic effect of some plant extracts and antibiotics against some microorganisms causing infectious diseases.
[27]
[30]
[24]
[32]
[35]
[26]
References
Science against microbial pathogens: communicating current research and technological advances
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A. Méndez-Vilas (Ed.)
©FORMATEX 2011
ET
AQ
ME
ME
ET
Salvadora persica Wall.
(Salvadoraceae)
Salvia officinalis L.
(Lamiaceae)
Tectona grandis L.
(Verbenaceae)
Thespesia populnea L.
(Malvaceae)
Vangueria spinosa Roxb.
(Rubiaceae)
Doxycycline, ofloxacin
Oxytetracycline
Tetracycline
Sodium benzoate, sodium nitrite, potassium
sorbate
Tetracycline, penicillin
Gentamicin, cephalothin, ceftriaxone, nystatin
[31]
[29]
[28]
[34]
[33]
Bacillus mycoides PMFKg-B), Bacillus subtilis PMFKg-B2,
Staphylococcus aureus PMFKg-B30, Agrobacterium tumefaciens
PMFKg-B11, Enterobacter cloacae PMFKg-B22, Erwinia carotovora
PMFKg-B31, Escherichia coli PMFKg-B26, Pseudomonas fluorescens
PMFKg-B28, Proteus sp. PMFKg-B20
Klebsiella pneumonia MTCC432, Psedomonas aeruginosa MTCC1688,
Proteus mirabilis MTCC425, Escherichia coli, MTCC729, Salmonella
typhimurium MTCC98, Citrobacter freondii MTCC1658, Serratia
marcescens MTCC97, Pichia pastoris MTCC34, Streptococcus species
MTCC389
Shigella sonei ATCC29930, Escherichia coli ATCC11229, Shigella
boydii ATCC8700, Rhodococcus terrae NCIM5126, Micrococcus
flavum NCIM2984, Flavobacterium devorans NCIM2581, Bacillus
licheniformis NCIM2468, Brevibacterium leuteum ATCC15830,
Salmonella typhi ATCC13313, Klebsiella pneumoniae ATCC11229,
Micrococcus leuteus ATCC9341, Shigella flexneri NCIM4924
Staphylococcus aureus MTCC2940, Escherischia coli MTCC739,
Pseudomonas aeruginosa MTCC2453, Klebsiella pneumoniae
MTCC432
[25]
Staphylococcus aureus
Micrococcus luteus LA2971, Bacillus megaterium NRS, Bacillus brevis
FMC3, Enterococcus faecalis ATCC15753, Pseudomonas pyocyaneus
DC127, Yersinia enterocolitica AU19, Mycobacterium smegmatis
CCM2067, Escherichia coli DM, Aeromonas hydrophila ATCC7966,
Staphylococcus aureus Cowan1, Streptococcus faecalis DC74,
Saccharomyces cerevisiae WET136, Kluvyeromyces fragilis DC98
ET: Ethanol; AQ: Aqueous; AC: Acetone; CH: Chloroform; EA: Ethyl acetate; ME: Methanol; EO: Essential oil
EO
Rosmarinus officinalis L.
(Lamiaceae),Coriandrum
sativum L. (Apiaceae) ,
Micromeria fruticosa L.
(Lamiaceae), Cumium
cyminum L. (Apiaceae),
Mentha piperita L.
(Lamiaceae)
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6. Final consideration
The review from this investigation indicates that the combination of medicinal plants extracts and known antibiotics
offers significant potential for the development of novel antimicrobial therapies and treatment of several diseases
caused by microorganisms. As seen from this review, the number of natural extracts acting in synergy with synthetic
drugs towards microbial species is large. This could be due to the understanding of the mechanism of action of drugs
against these organisms and proper selection of natural compounds. There is a need for more studies concerning the
molecular basis of synergistic interactions, to understand the synergistic mechanism which is fundamental to the
development of pharmacological agents to treat bacterial infections using medicinal plants. Hence, research should be
focused towards this direction to identify more medicinal plants which exhibit synergistic behaviour.
Acknowledgements The authors thank Prof. S.P. Singh, Head, Department of Biosciences, Saurashtra University, Rajkot, Gujarat,
India for providing excellent research facilities. One of the authors, Ms. Kalpna Rakholiya, is thankful to University Grants
Commission, New Delhi, India for providing financial support.
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