Synergistic Antibacterial Activity of Fig (Ficus carica) Leaves Extract

Kor. J. Microbiol. Biotechnol.
Vol. 38, No. 4, 405–413 (2010)
Synergistic Antibacterial Activity of Fig (Ficus carica) Leaves Extract
Against Clinical Isolates of Methicillin-resistant Staphylococcus aureus
1
Lee, Young-Soo1 and Jeong-Dan Cha2*
Department of Dental Hygiene, Sunmoon University, Asan 336-708, Korea
Department of Dental Hygiene, College of Natural Sciences, Dongeui University, Busan 614-714, Korea
2
Fig (Ficus carica L.) belongs to the mulberry tree (Moraceae) which is one of the oldest fruits in the world. It
has been used as a digestion promoter and a cure for ulcerative inflammation and eruption in Korea. The
present study investigated the antimicrobial activity of methanol (MeOH) extract of fig leaves against methicillin-resistant Staphylococcus aureus (MRSA) isolated in clinic. The MeOH extract (MICs, 2.5 to 20 mg/mL;
MBCs, 5 to 20 mg/mL) was demonstrated as antibacterial activity in isolates MRSA 1-20. The administration
of the MeOH extract in combination with oxacillin or ampicillin induced a reduction of ≥4-8-fold in all tested
bacteria, which was considered to be synergistic based on a FICI of ≤ 0.375-0.5. Furthermore, time-kill study
was found that a combination of MeOH extract with oxacillin or ampicillin produced a more rapid decrease in
the concentration of bacteria CFU/mL than MeOH extract alone. The results suggest that fig leaves could be
employed as a natural antibacterial agent in MRSA infection care products.
Key words: Ficus carica (fig), methicillin-resistant Staphylococcus aureus, antibacterial activity, minimum
inhibitory concentration, minimum bactericidal concentration, synergistic effect
Introduction
Methicillin-resistant Staphylococcus aureus (MRSA) is
one of the most important nosocomial pathogens of the past
two decades [1, 16]. MRSA which is resulted from the
selective pressure of antibiotics currently used has increased relentlessly and well recognized as a global nosocomial problem in recent years [11, 16]. It has now emerged
as the predominant and serious pathogenic bacterium,
leading to high morbidity and mortality [11, 25]. MRSA
normally possesses a multidrug-resistant gene that causes it
to be resistant to β-lactams, aminoglycosides, fluoroquinolones and macrolides [6, 13, 25]. Many studies have
been conducted to evaluate natural products as novel antibiotic substances against MRSA and to develop antibiotics
that would be advantageous for combating the therapeutic
problems associated with MRSA [2, 5, 15]. The importance
of Korean herbal medicines has now been increasingly
recognized.
Ficus carica L. is a sort of deciduous tree which belongs
*Corresponding author
Tel: 82-51-890-2688, Fax: 82-51-890-2623
E-mail: [email protected]
to the Moraceae family. Its fruit is generally referred as figs
which have been used as food and medicine for several
centuries [8, 14]. Its fruit, root and leaves are used in the
native system of medicine in different disorders, such as
colic, indigestion, diarrhea, sore throats, coughs, bronchial
problems, inflammatory, cardiovascular disorders, ulcerative diseases, and cancers [3, 8, 14, 17, 19]. Phytochemical
studies revealed the presence of numerous bioactive compounds: arabinose, β-amyrins, β-carotines, glycosides, βsetosterols and xanthotoxol [7, 8]. The 6-O-acyl-β-dglucosyl-β-sitosterols along with its palmitoyl, linoleyl,
stearyl and oleyl derivatives isolated from the fruit of F.
carica exhibited strong cytotoxic effect [7, 8, 19]. It contains the highest levels of polyphenols, flavonoids, and
anthocyanins and exhibits the highest antioxidant capacity
[18, 21, 23]. F. carica has been reported to include antioxidant, antiviral, antibacterial, antiinflammation, haemostatic, hypoglycemic, hypocholesterolaemic, cancer suppressive, and anthelmintic effects [3, 8, 10, 17, 18, 21, 23, 24].
However, the plant has not been studied for antibacterial
activity against MRSA.
In the present study, the antimicrobial activities of
MeOH extract from fig leaves against methicillin-resistant
Staphylococcus aureus isolated in a clinic were assessed
406
LEE AND CHA
using the microdilution method and the checkerboard and
time-kill methods to evaluate the synergistic effects of a
combination with oxacillin or ampicillin.
Materials and Methods
Plant material and preparation of methanol extract
Fig leaves were collected in September 2005 from the
Samho farm of Yeongam-gun in Korea. The identity was
confirmed by Dr. Bong-Seop Kil, College of Natural
Science, Wonkwang University. The voucher specimens
(DJ-05-F1) were deposited at the Herbarium of the College
of Natural Science, Wonkwang University. The dried and
powered leaves (1.2 kg) of fig were extracted by repeated
refluxing with methanol (MeOH) (2×6 L) for 4h at 80oC.
The combined MeOH extract (12 L) was clarified by
filtration and evaporated to obtain dark green syrup (210
g).
Minimum inhibitory concentration/minimum bactericidal concentration assay
We utilized 20 isolates of methicillin-resistant Staphylococcus aureus isolated from the Wonkwang University
Hospital, as well as standard strains of methicillin-sensitive
S. aureus (MSSA) ATCC 25923 and methicillin-resistant S.
aureus (MRSA) ATCC 33591 [4, 12]. The minimum inhibitory concentration (MIC) was determined as the lowest
concentration of test samples that resulted in a complete
inhibition of visible growth in the broth. Following 10%
CO2 incubation of MIC plates, the minimum bactericidal
concentration (MBC) was determined on the basis of the
lowest concentration of the MeOH extract that kill 99.9%
of the test bacteria by plating out onto each appropriate agar
plate.
Checker board dilution test
The synergistic effects of the MeOH extract, which
exhibited the highest antimicrobial activity and antibiotics,
were assessed by the checkerboard test as previously described [4, 5]. The antimicrobial combinations assayed
included the MeOH extract plus ampicillin or oxacillin.
The fractional inhibitory concentration (FIC) index is the
sum of the FICs of each of the drugs, which in turn is defined as the MIC of each drug when it is used in combination divided by the MIC of the drug when it is used alone.
The interaction was defined as synergistic if the FIC index
was less than or equal to 0.5, additive if the FIC index was
greater than 0.5 and less than or equal 1.0, indifferent if the
FIC index was greater than 1.0 and less than or equal to
2.0, and antagonistic if the FIC index was greater than 2.0
[5].
Time-kill curves
The bactericidal activities of the drugs evaluated in this
study were also evaluated using time-kill curves constructed using the isolated and reference strains. Tubes containing the MeOH extract and bacteria were incubated at
37oC, and viable counts were conducted at 0, 0.5, 1, 2, 3,
4, 5, 6, 12, and 24 h after the addition of the antimicrobial
agents by plating aliquots of the samples on agar and
subsequent incubation for 24 hr at 37oC. Cultures with an
initial cell density of 1.5~4.0×107 CFU/mL were exposed
to the MBC of the MeOH extract alone, or with ampicillin
or oxacillin. All experiments were repeated several times
and colony counts were conducted in triplicate, after which
the means were determined.
Results and Discussion
The antibacterial activity of the MeOH extract of fig
leaves are shown in Table 1 and 2. The MeOH extract
exhibited antibacterial effects against all of the tested
bacteria (MIC, 2.5 to 20 mg/mL; MBC, 5 to 20 mg/mL).
The MIC and MBC for ampicillin was found to be either
2 to 1024 µg/mL; 2 to 2048 µg/mL, while that of oxacillin
was either 0.25 to 32 µg/mL; 0.5 to 64 µg/mL. The synergistic effects of the MeOH extract administered in combination with oxacillin or ampicillin are shown in Tables 1
and 2, respectively. When administered in combination
with the MeOH extract, the MIC for oxacillin was reduced
≥4-8-fold when tested against all of the bacteria evaluated
in this study, with the exception of MSSA. These findings
indicate that a synergistic effect based on a FICI of ≤
0.375-0.5 (Table 1). Furthermore, the MeOH extract with
ampicillin was found to be synergistic (FICI ≤ 0.375-0.5)
against all of the bacteria evaluated here, with the exception of MRSA 13 and 17, for which the effects were
additive (FICI ≤ 0.75) (Table 2).
The synergistic effects of the MeOH extract with oxacillin or ampicillin administered were confirmed by timekill curve experiments (Fig. 1-3). Cultures of each strain of
bacteria with a cell density of 107 CFU/mL were exposed
SYNERGISTIC ACTIVITY OF MRSA
407
Table 1. Synergistic effects of the methanol extract (MeOH) of fig leaves with oxacillin in isolated MRSA and reference MSSA
(ATCC25923) and MRSA(ATCC33591) strains.
MIC/MBC (µg/mL)
FIC1)
FICI2)
Outcome
1.25/2.5
0.0625/0.125
0.5/0.5
0.25/0.25
0.75/0.75
Additive/ Additive
10/10
16/16
2.5/5
4/8
0.25/0.5
0.25/0.5
0.5/1.0
Synergistic/ Additive
MeOH
Oxacillin
10/20
4/4
2.5/5
1/2
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
MRSA 2
MeOH
Oxacillin
5/10
8/16
1.25/2.5
2/4
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 3
MeOH
Oxacillin
20/20
4/4
5/10
1/2
0.25/0.5
0.25/0.5
0.5/1.0
Synergistic/ Additive
MRSA 4
MeOH
Oxacillin
10/20
16/16
2.5/5
4/8
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
MRSA 5
MeOH
Oxacillin
5/5
16/32
1.25/1.25
4/8
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 6
MeOH
Oxacillin
10/20
8/16
2.5/10
2/4
0.25/0.5
0.25/0.25
0.5/0.75
Synergistic/ Additive
MRSA 7
MeOH
Oxacillin
5/10
16/32
1.25/2.5
2/8
0.25/0.25
0.125/0.25
0.375/0.5
Synergistic/ Synergistic
MRSA 8
MeOH
Oxacillin
20/20
4/8
5/10
1/4
0.25/0.5
0.25/0.5
0.5/1.0
Synergistic/ Additive
MRSA 9
MeOH
Oxacillin
5/10
16/32
1.25/2.5
4/8
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 10
MeOH
Oxacillin
10/20
8/16
2.5/5
2/4
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 11
MeOH
Oxacillin
20/20
16/16
5/5
4/4
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 12
MeOH
Oxacillin
20/20
32/32
5/10
8/16
0.25/0.5
0.25/0.5
0.5/1.0
Synergistic/ Additive
MRSA 13
MeOH
Oxacillin
10/20
32/64
4/8
8/16
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 14
MeOH
Oxacillin
20/20
16/32
5/10
4/8
0.25/0.5
0.25/0.25
0.5/0.75
Synergistic/ Additive
MRSA 15
MeOH
Oxacillin
10/10
8/16
2/4
2/2
0.25/0.25
0.25/0.125
0.5/0.375
Synergistic/ Synergistic
MRSA 16
MeOH
Oxacillin
10/20
16/32
2.5/5
4/4
0.25/0.25
0.25/0.125
0.5/0.375
Synergistic/ Synergistic
MRSA 17
MeOH
Oxacillin
20/20
8/16
5/10
2/4
0.25/0.5
0.25/0.25
0.5/0.75
Synergistic/ Additive
MRSA 18
MeOH
Oxacillin
20/20
4/16
5/5
0.5/4
0.25/0.25
0.125/0.25
0.375/0.5
Synergistic/ Synergistic
MRSA 19
MeOH
Oxacillin
5/10
4/8
1.25/5
1/2
0.25/0.5
0.25/0.25
0.5/0.75
Synergistic/ Additive
MRSA 20
MeOH
Oxacillin
10/20
16/16
2.5/5
4/8
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
Samples
Agent
MSSA ATCC 25923 3)
Alone
Combination
MeOH6)
Oxacillin
2.5/5
0.25/0.5
MRSA ATCC 33591 4)
MeOH
Oxacillin
MRSA 15)
1)
The fractional inhibitory concentration (FIC)
the FIC index (FICI)
3)
MSSA (ATCC 25923): reference strain methicillin-sensitive Staphylococcus aureus.
4)
MRSA (ATCC 33591): reference strain methicillin-resistant Staphylococcus aureus.
5)
MRSA (1-20): Methicillin-resistant Staphylococcus aureus isolated in clinic.
6)
Methanol extract of fig leaves
2)
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Table 2. Synergistic effects of the methanol extract (MeOH) of fig leaves with ampicillin in isolated MRSA and reference MSSA
(ATCC25923) and MRSA(ATCC33591) strains.
FICI2)
Outcome
0.625/1.25
0.5/1
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
10/10
1024/2048
2.5/2.5
256/256
0.25/0.25
0.25/0.125
0.5/0.375
Synergistic/ Synergistic
MeOH
Ampicillin
10/20
1024/2048
2.5/5
256/512
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 2
MeOH
Ampicillin
5/10
128/128
1.25/2.5
32/64
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
MRSA 3
MeOH
Ampicillin
20/20
1024/2048
5/5
256/256
0.25/0.25
0.25/0.125
0.5/0.375
Synergistic/ Synergistic
MRSA 4
MeOH
Ampicillin
10/20
128/256
2.5/5
32/64
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 5
MeOH
Ampicillin
5/5
128/128
1.25/2.5
32/64
0.25/0.5
0.25/0.5
0.5/1.0
Synergistic/ Additive
MRSA 6
MeOH
Ampicillin
10/20
128/128
2.5/5
32/32
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 7
MeOH
Ampicillin
5/10
128/128
1.25/2.5
32/64
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
MRSA 8
MeOH
Ampicillin
20/20
128/128
5/10
32/64
0.25/0.5
0.25/0.5
0.5/1.0
Synergistic/ Additive
MRSA 9
MeOH
Ampicillin
5/10
128/128
2.5/5
32/64
0.5/0.5
0.25/0.5
0.75/1.0
Additive/ Additive
MRSA 10
MeOH
Ampicillin
10/20
64/64
2.5/5
16/32
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
MeOH
Ampicillin
MeOH
Ampicillin
20/20
64/128
20/20
128/256
5/10
16/32
5/10
32/64
0.25/0.5
0.25/0.25
0.25/0.25
0.25/0.25
0.5/0.75
Synergistic/ Additive
0.5/0.5
Synergistic/ Synergistic
MeOH
Ampicillin
10/20
64/128
5/10
16/32
0.5/0.5
0.25/0.25
0.75/0.75
Additive/ Additive
MeOH
Ampicillin
MeOH
Ampicillin
20/20
128/128
10/10
64/128
5/10
32/64
2.5/2.5
16/32
0.25/0.5
0.25/0.5
0.25/0.25
0.25/0.25
0.5/1.0
Synergistic/ Additive
0.5/0.5
Synergistic/ Synergistic
MeOH
Ampicillin
10/20
64/64
2.5/5
16/32
0.25/0.25
0.25/0.5
0.5/0.75
Synergistic/ Additive
MeOH
Ampicillin
MeOH
Ampicillin
20/20
64/64
20/20
64/64
10/10
16/32
5/10
16/32
0.5/0.5
0.25/0.5
0.25/0.5
0.25/0.5
0.75/1.0
Additive/ Additive
0.5/1.0
Synergistic/ Additive
MRSA 19
MeOH
Ampicillin
5/10
64/64
1.25/2.5
16/16
0.25/0.25
0.25/0.25
0.5/0.5
Synergistic/ Synergistic
MRSA 20
MeOH
Ampicillin
10/20
128/128
1.25/2.5
32/32
0.125/0.125
0.25/0.25
0.375/0.375
Synergistic/ Synergistic
Agent
MSSA ATCC 25923 3)
Alone
Combination
MeOH6)
Ampicillin
2.5/5
2/2
MRSA ATCC 33591 4)
MeOH
Ampicillin
MRSA 15)
MRSA 11
MRSA 12
MRSA 13
MRSA 14
MRSA 15
MRSA 16
MRSA 17
MRSA 18
1)
MIC/MBC (µg/mL)
FIC1)
Samples
The fractional inhibitory concentration (FIC)
the FIC index (FICI)
3)
MSSA (ATCC 25923): reference strain Methicillin-sensitive Staphylococcus aureus.
4)
MRSA (ATCC 33591): reference strain Methicillin-resistant Staphylococcus aureus.
5)
MRSA (1-20): Methicillin-resistant Staphylococcus aureus isolated in clinic.
6)
Methanol extract of fig leaves
2)
SYNERGISTIC ACTIVITY OF MRSA
409
Fig. 1. Time-kill curves of MBC of the methanol extract alone and its combination with MBC of oxacillin or ampicillin against isolates MRSA (1-6) and reference strains. Bacteria were incubated with the methanol extract (MeOH) alone (●) and with oxacillin (○) or
with ampicillin (▲ ) over time. Data points are the mean values±S.E.M. of six experiments. CFU, colony-forming units.
to the MBC of MeOH extract alone or with oxacillin or
ampicillin. We found that a combination of MeOH extract
with oxacillin or ampicillin was produced as a more rapid
decrease in MBC than MeOH alone. The growth of the
tested bacteria was completely attenuated after 2-5 hr of
treatment with the MBC of the MeOH extract, regardless
of whether it was administered alone or with oxacillin or
ampicillin.
The phytochemical analysis reveals that the aqueous
extract of ripe dried fruit of fig contains alkaloids, flavonoids, coumarins, saponins, and terpenes [8, 22, 23]. Some
phenolic compounds, with reported pharmacological properties have already been isolated from fig leaves, namely
furanocoumarins like psoralen and bergapten, flavonoids
like rutin, quercetin, and luteolin, phenolic acids like
ferrulic acid, and also phytosterols like taraxasterol [22,
23]. Phenolic and flavonoid compounds constitute an
important class of phytochemicals which possess diverse
410
LEE AND CHA
Fig. 2. Time-kill curves of MBC of the methanol extract alone and its combination with MBC of oxacillin or ampicillin against isolates MRSA (7-14). Bacteria were incubated with the methanol extract (MeOH) alone ( ●) and with oxacillin ( ○) or with ampicillin ( ▲ )
over time. Data points are the mean values ± S.E.M. of six experiments. CFU, colony-forming units.
biological activities like astringent, antioxidant, anticancer,
anti-inflammation, and antibacterial activity, etc [5, 8, 20,
21, 23]. The results of the antibacterial activity showed that
the MeOH extract of fig leaves exhibited inhibitory activities against isolates MRSA and reference strains (MIC,
2.5 to 20 mg/mL; MBC, 5 to 20 mg/mL). The synergistic
effect of MeOH extract with oxacillin or ampicillin was
shown as reduced ≥4-8-fold in most of tested MRSA,
producing a synergistic effect as defined by FICI ≤ 0.375-
0.5. Furthermore, combination of the MeOH extract with
oxacillin or ampicillin showed a more rapid decrease in
MBC than MeOH extract alone.
MRSA is resistant to methicillin and other β-lactams, as
well as to a host of other antibacterial agents, including
macrolide [13]. MRSA is very dangerous, and can produce
serious medical problems because it causes many common
infectious diseases and often acquires multi-drug resistance
[11, 25]. Several studies have demonstrated that phenolic
SYNERGISTIC ACTIVITY OF MRSA
411
Fig. 3. Time-kill curves of MBC of the methanol extract alone and its combination with MBC of oxacillin or ampicillin against isolates MRSA (15-20). Bacteria were incubated with the methanol extract (MeOH) alone (●) and with oxacillin (○) or with ampicillin (▲ )
over time. Data points are the mean values±S.E.M. of six experiments. CFU, colony-forming units.
and flavonoid compounds produced by plants exert antibacterial activity against MRSA [5, 8, 9]; therefore, it is
likely that the phenolic and flavonoid compounds in fig
leaves may be related, in part, to the antibacterial effects
observed in the present study.
In the present study, we verified the synergistic activity
of fig leaves extracts based on their inhibition of the growth
of MRSA. Furthermore, we demonstrated that these compounds exerted synergistic effects when administered with
oxacillin or ampicillin. These findings suggest that fig leaves
could be employed as a natural antibacterial agent in
MRSA infection care products.
Acknowledgement
This paper was supported in part by research funds of
Sunmoon University and National Research Foundation of
Korea Grant funded by the Korean Government (KRF2008-331-E00348).
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(Received June 29, 2010/Accepted Oct. 5, 2010)
SYNERGISTIC ACTIVITY OF MRSA
국문초록
병원내에서 분리된 메티실린내성 황색포도상구균에 대한 무화과잎 추출물의 항미생물효과
이영수1·차정단2*
1
선문대학교 치위생학과, 2동의대학교 치위생학과
무화과는 뽕나무 과에 속하며 세계에서 가장 오래된 과일 중 하나이고, 국내에서는 주로 소화장애, 염증성궤양 그
리고 가려움증 등에 사용되어 왔다. 본 연구에서는 무화과 잎을 메탄올로 추출한 후 임상진료실에서 분리된 메티실
린 내성 황색포도상구균(MRSA)에 대한 항균활성을 보았다. 그 결과 분리된 MRSA 1-20에서 최소억제농도 (MIC)
는 2.5 mg/mL에서 20 mg/mL 농도로 측정되었으며, 최소살균농도(MBC)는 5 mg/mL에서 20 mg/mL 농도로 관찰되
었다. Oxacillin이나 ampicillin과 병용투여 시 4-8배 이상의 MIC/MBC농도가 감소되었으며, FICI 값도 0.0375-0.5
이하로 병용효과를 나타내었다. 더불어 메탄올추출물 단독 사용시 보다 항생제와 병용투여 시 빠른 사멸효과를 보였
다. 결론적으로 무화과 잎이 메티실린 내성 황색포도상구균에 항균활성을 나타냄을 확인하였으며, 메티실린 내성 황
색포도상구균 감염에 천연 치료제로서의 가능성을 확인하였다.
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