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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.
520 ©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances 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.
521©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances 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
522 ©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances A. Méndez-Vilas (Ed.)______________________________________________________________________________
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.
523©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances A. Méndez-Vilas (Ed.)_______________________________________________________________________________
T
able
1 L
ist o
f so
me
plan
t ext
ract
s sh
owin
g an
timic
robi
al a
ctiv
ity
agai
nst a
pan
el o
f m
icro
orga
nism
s ca
usin
g in
fect
ious
dis
ease
s.
Pla
nt
Nam
e (F
amily
) P
art
use
d E
xtra
ct
Mic
roor
gan
ism
s R
efer
ence
And
rogr
aphi
s pa
nicu
lata
(B
urm
.f.)
Wal
l. (A
cant
hace
ae)
Aer
ial p
art
CH
, CH
+ H
Cl (
1M)
Stap
hylo
cocc
us a
ureu
s, B
acill
us s
ubtil
is,
Ent
erob
acte
r fa
ecal
is,
Stap
hylo
cocc
us
epid
erm
idis
, E
sche
rich
ia c
oli,
Pse
udom
onas
aer
ugin
osa,
Kle
bsie
lla p
neum
onia
e,
Salm
onel
la ty
phim
uriu
m, E
nter
obac
ter
cloa
cae
[36]
Cin
nam
omum
iner
s S
chae
ff.
(Lau
race
ae)
Lea
ves
ME
St
aphy
loco
ccus
aur
eus
[37]
Coc
cini
a gr
andi
s L
. (C
ucur
bita
ceae
) L
eave
s E
T, A
Q
Can
dida
al
bica
ns,
Asp
ergi
llus
nige
r,
Bac
illus
su
btili
s,
Bac
illus
pu
milu
s,
Ent
eroc
occu
s fa
ecal
is,
Bac
illus
lic
heni
form
is,
Stap
hylo
cocc
us
aure
us,
Stre
ptoc
occu
s fa
ecal
is,
Shig
ella
bo
ydii-
Typ
e12,
Sh
igel
la
flexn
eri9
, Sh
igel
la
dyse
nter
iae-
3 , P
seud
omon
as a
erug
inos
a , E
sche
rich
ia c
oli,
Salm
onel
la ty
phi-
62 ,
Salm
onel
la c
hole
raes
uis-
36 ,
Shig
ella
boy
dii-
8, S
hige
lla fl
exne
ri N
ICE
D, S
hige
lla
sonn
ei
[38]
Dio
spyr
os e
benu
m R
oxb.
(E
bena
ceae
) L
eave
s P
E, E
A, M
E, A
Q
Bac
illus
sub
tilis
, Sta
phyl
ococ
cus
aure
us, P
seud
omon
as a
erug
inos
a,
Salm
onel
la ty
phim
uriu
m, E
nter
obac
ter
aero
gene
s [3
9]
Euc
alyp
tus
citr
iodo
ra H
k (M
yrta
ceae
) L
eave
s D
O, M
E, A
C, E
T, A
Q
Pse
udom
onas
ps
eudo
alca
ligen
es,
Pro
teus
vu
lgar
is,
Citr
obac
ter
freu
ndii,
St
aphy
loco
ccus
sub
flava
, Bac
illus
meg
ater
ium
, Ent
erob
acte
r ae
roge
nes
[12]
Hyp
tis m
artiu
sii B
enth
. (L
abia
tae)
A
eria
l par
t E
T (
95%
) E
sche
rich
ia c
oli
[40]
524 ©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances A. Méndez-Vilas (Ed.)______________________________________________________________________________
Man
gife
ra in
dica
L.
(Ana
card
iace
ae)
See
d P
E, C
H, E
A, A
C, M
E
Stap
hylo
cocc
us
aure
us,
Stap
hylo
cocc
us
epid
erm
idis
, B
acill
us
subt
ilis,
M
icro
cocc
us
flavu
s,
Esc
heri
chia
co
li,
Pse
udom
onas
ae
rugi
nosa
, K
lebs
iella
pn
eum
onia
e,
Pro
teus
vu
lgar
is,
Pro
teus
m
irab
ilis,
C
itrob
acte
r fr
eund
ii,
Salm
onel
la t
yphi
mur
ium
, C
andi
da a
lbic
ans,
Can
dida
tro
pica
lis,
Cry
ptoc
occu
s lu
teol
us
[41]
Mer
rem
ia e
mar
gina
ta H
allie
r f.
(c
onvo
lvul
acea
e)
Lea
ves
PE
, ME
, AQ
St
aphy
loco
ccus
au
reus
, B
acill
us
cere
us,
Esc
heri
chia
co
li,
Pse
udom
onas
ae
rugi
nosa
[4
2]
Met
aseq
uoia
gly
ptos
trob
oide
s M
iki e
x H
u (C
upre
ssac
eae)
C
ones
E
A
Lis
teri
a m
onoc
ytog
enes
, Sa
lmon
ella
ty
phim
uriu
m,
Salm
onel
la
ente
ritid
is,
Esc
heri
chia
col
i, E
nter
obac
ter
aero
gene
s, S
taph
yloc
occu
s au
reus
[4
3]
Pip
er r
ibes
oide
s W
all
(Pip
erac
eae)
R
oot
ME
St
aphy
loco
ccus
aur
eus
[44]
Pol
yalth
ia lo
ngifo
lia (
Sonn
.) T
hw.
var.
Pen
dula
(A
nnon
acea
e)
Lea
ves
ME
, AC
, DO
Stap
hylo
cocc
us s
p.-1
3, S
. au
reus
, S.
epi
derm
idis
, S.
sub
fava
, B
acill
us c
ereu
s, B
. su
btil
is,
B.
meg
ater
ium
, M
. fla
vus,
P
seud
omon
as
sp.-
16,
P.
aeru
gino
sa,
P.
test
oste
rone
, P
. ps
eudo
alca
ligen
es,
E.
coli-
15,
E.
coli,
Ent
erob
acte
r sp
.-2,
E.
aero
gene
s,
Kle
bsie
lla
sp.-
5,
K.
pneu
mon
iae,
P
rote
us
sp.-
2,
P.
mir
abil
is,
P.
vulg
aris
, P
. m
orga
nii,
Pro
vide
ncia
sp
.-1,
C
itrob
acto
r sp
.-2,
C
. fr
eund
ii,
Alc
alig
enes
fec
alis
, Sa
lmon
ella
typ
him
uriu
m,
Can
dida
sp.
-5,
C.
albi
cans
-2,
C.
glab
rata
, C
. tr
opic
alis
, C
. ap
icol
a,
Cry
ptoc
occu
s ne
ofor
man
s,
C.
lute
olus
, T
rich
ospo
ran
beig
elii,
Asp
ergi
llus
flavu
s, A
. can
didu
s A
. nig
er
[45]
Pso
rale
a co
rylif
olia
L.
(Fab
acea
e)
See
d, a
eria
l pa
rt
PE
, ME
, AC
, DO
, D
MF
Stap
hylo
cocc
us
epid
erm
idis
, E
nter
obac
ter
aero
gene
s,
Bac
illus
m
egat
eriu
m,
Pro
teus
mor
gani
i, A
lcal
igen
es fe
calis
[4
6]
ET
: Eth
anol
; AQ
: Aqu
eous
; AC
: Ace
tone
; CH
: Chl
orof
orm
; EA
: Eth
yl a
ceta
te; M
E: M
etha
nol;
HC
L: H
ydro
chlo
ric
acid
; PE
: Pet
role
um e
ther
; DO
: 1,4
-dio
xan;
DM
F: N
,N-d
imet
hylf
orm
amid
e
525©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances A. Méndez-Vilas (Ed.)_______________________________________________________________________________
T
able
2 S
yner
gist
ic e
ffec
t of
som
e pl
ant e
xtra
cts
and
anti
biot
ics
agai
nst s
ome
mic
roor
gani
sms
caus
ing
infe
ctio
us d
isea
ses.
Pla
nt
nam
e E
xtra
ct
An
tib
ioti
cs
Mic
roor
gan
ism
s R
efer
ence
s
Eup
horb
ia h
irta
L.
(Eup
horb
iace
ae)
ME
E
ryth
rom
ycin
St
aphy
loco
ccus
aur
eus
[26]
Fic
us e
xasp
erat
a V
ahl
(Mor
acea
e)
ET
G
enta
mic
in,
tetr
acyc
line
, am
pici
llin
, ch
lora
mph
enic
ol,
eryt
hrom
ycin
, sa
mtr
im,
pro.
peni
cilli
n E
sche
rich
ia c
oli,
Stap
hylo
cocc
us a
lbus
[3
5]
Hel
ichr
ysum
long
ifoliu
m
DC
. (A
ster
acea
e)
AC
, C
H,
EA
, M
E,
AQ
Pen
icil
lin
G
sodi
um,
amox
icil
lin,
ch
lora
mph
enic
ol,
cipr
oflo
xaci
n ox
ytet
racy
clin
e, e
ryth
rom
ycin
Pse
udom
onas
ae
rugi
nosa
A
TC
C19
582,
St
aphy
loco
ccus
au
reus
A
TC
C65
38,
Bac
illu
s ce
reus
A
TC
C10
702,
B
acill
us
pum
ilus
AT
CC
1488
4, P
rote
us v
ulga
ris
AT
CC
6830
, Aci
neto
bact
er c
alca
ocet
icus
an
itrat
us
CS
IR,
Stap
hylo
cocc
us
aure
us
OK
OH
1,
Shig
ella
fle
xine
ri,
Salm
onel
la s
pp.,
Mic
roco
ccus
kri
stin
ae
[32]
Man
gife
ra in
dica
L.
(Ana
card
iace
ae)
ET
N
orfl
oxac
in, t
etra
cycl
ine,
ery
thro
myc
in
Stap
hylo
cocc
us a
ureu
s [2
4]
Rhu
s co
riar
ia L
. (A
naca
rdia
ceae
), P
sidi
um
guaj
ava
L. (
Myr
tace
ae),
L
awso
nia
iner
mis
L.
(Lyt
hrac
eae)
, Sa
crop
oter
ium
spi
nosu
m L
. (R
osac
eae)
ET
O
xyte
trac
ycli
n H
Cl,
enro
flox
acin
,
gent
amic
in s
ulph
ate,
sul
phad
imet
hoxi
n St
aphy
loco
ccus
aur
eus
[30]
Rhu
s co
riar
ia L
. (A
naca
rdia
ceae
),
Sacr
opot
eriu
m s
pino
sum
L.
(Ros
acea
e), R
osa
dam
asce
ne M
ill.
(Ros
acea
e)
ET
O
xyte
trac
ycli
ne H
Cl,
peni
cill
in G
, ce
phal
exin
, su
lfad
imet
hoxi
ne a
s so
dium
, enr
oflo
xaci
n P
seud
omon
as a
erug
inos
a [2
7]
526 ©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances A. Méndez-Vilas (Ed.)______________________________________________________________________________
Ros
mar
inus
offi
cina
lis L
. (L
amia
ceae
),C
oria
ndru
m
sativ
um L
. (A
piac
eae)
, M
icro
mer
ia fr
utic
osa
L.
(Lam
iace
ae),
Cum
ium
cy
min
um L
. (A
piac
eae)
, M
enth
a pi
peri
ta L
. (L
amia
ceae
)
EO
G
enta
mic
in, c
epha
loth
in, c
eftr
iaxo
ne, n
ysta
tin
Mic
roco
ccus
lut
eus
LA
2971
, Bac
illu
s m
egat
eriu
m N
RS,
Bac
illu
s br
evis
F
MC
3, E
nter
ococ
cus
faec
alis
AT
CC
1575
3, P
seud
omon
as p
yocy
aneu
s D
C12
7,
Yer
sini
a en
tero
colit
ica
AU
19,
Myc
obac
teri
um
smeg
mat
is
CC
M20
67,
Esc
heri
chia
col
i D
M,
Aer
omon
as h
ydro
phila
AT
CC
7966
, St
aphy
loco
ccus
au
reus
C
owan
1,
Stre
ptoc
occu
s fa
ecal
is
DC
74,
Sacc
haro
myc
es c
erev
isia
e W
ET
136,
Klu
vyer
omyc
es fr
agili
s D
C98
[25]
Sal
vado
ra p
ersi
ca W
all.
(Sal
vado
race
ae)
ET
T
etra
cycl
ine,
pen
icill
in
Stap
hylo
cocc
us a
ureu
s [3
1]
Salv
ia o
ffici
nalis
L.
(Lam
iace
ae)
AQ
S
odiu
m
benz
oate
, so
dium
ni
trite
, po
tass
ium
so
rbat
e
Bac
illus
m
ycoi
des
PM
FK
g-B
),
Bac
illus
su
btili
s P
MF
Kg-
B2,
St
aphy
loco
ccus
au
reus
PM
FK
g-B
30,
Agr
obac
teri
um
tum
efac
iens
P
MF
Kg-
B11
, E
nter
obac
ter
cloa
cae
PM
FKg-
B22
, E
rwin
ia c
arot
ovor
a P
MF
Kg-
B31
, E
sche
rich
ia c
oli
PM
FK
g-B
26,
Pse
udom
onas
flu
ores
cens
P
MF
Kg-
B28
, Pro
teus
sp.
PM
FK
g-B
20
[29]
Tec
tona
gra
ndis
L.
(Ver
bena
ceae
) M
E
Tet
racy
clin
e
Kle
bsie
lla p
neum
onia
MT
CC
432,
Pse
dom
onas
aer
ugin
osa
MT
CC
1688
, P
rote
us m
irab
ilis
MT
CC
425,
Esc
heri
chia
col
i, M
TC
C72
9, S
alm
onel
la
typh
imur
ium
M
TC
C98
, C
itrob
acte
r fr
eond
ii M
TC
C16
58,
Serr
atia
m
arce
scen
s M
TC
C97
, P
ichi
a pa
stor
is M
TC
C34
, St
rept
ococ
cus
spec
ies
MT
CC
389
[28]
Thes
pesi
a po
puln
ea L
. (M
alva
ceae
) M
E
Oxy
tetr
acyc
line
Shig
ella
so
nei
AT
CC
2993
0,
Esc
heri
chia
co
li
AT
CC
1122
9,
Shig
ella
bo
ydii
AT
CC
8700
, R
hodo
cocc
us
terr
ae
NC
IM51
26,
Mic
roco
ccus
fla
vum
N
CIM
2984
, F
lavo
bact
eriu
m
devo
rans
N
CIM
2581
, B
acill
us
liche
nifo
rmis
N
CIM
2468
, B
revi
bact
eriu
m
leut
eum
A
TC
C15
830,
Sa
lmon
ella
ty
phi
AT
CC
1331
3,
Kle
bsie
lla
pneu
mon
iae
AT
CC
1122
9,
Mic
roco
ccus
leut
eus
AT
CC
9341
, Shi
gella
flex
neri
NC
IM49
24
[34]
Van
guer
ia s
pino
sa R
oxb.
(R
ubia
ceae
) E
T
Dox
ycyc
line
, ofl
oxac
in
Stap
hylo
cocc
us
aure
us
MT
CC
2940
, E
sche
risc
hia
coli
M
TC
C73
9,
Pse
udom
onas
ae
rugi
nosa
M
TC
C24
53,
Kle
bsie
lla
pneu
mon
iae
MT
CC
432
[33]
ET
: Eth
anol
; AQ
: Aqu
eous
; AC
: Ace
tone
; CH
: Chl
orof
orm
; EA
: Eth
yl a
ceta
te; M
E: M
etha
nol;
EO
: Ess
entia
l oil
527©FORMATEX 2011
Science against microbial pathogens: communicating current research and technological advances A. Méndez-Vilas (Ed.)_______________________________________________________________________________
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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