Iraqi J Pharm Sci, Vol.30(2) 2021 Synergistic effects of S. striata extract and antibiotics
DOI: https://doi.org/10.31351/vol30iss2pp219-224
219
Evaluation of Synergistic Antibacterial Effect of Combined Scrophularia
striata Extract and Antibiotics Against Pseudomonas aeruginosa and
Methicillin -Resistant Staphylococcus aureus
Shabnam Pourmoslemi*, Shirin Moradkhani**, Pari Tamri***,1and Sahar Foroughinia*
*Department of Pharmaceutics, School of Pharmacy, Medicinal Plants and Natural Products Research Center,
Hamadan University of Medical Sciences Hamadan, Iran
**Department of Pharmacognosy, School of Pharmacy, Medicinal Plants and Natural Products Research Center,
Hamadan University of Medical Sciences Hamadan, Iran
***Department of Pharmacology &Toxicology, School of Pharmacy, Medicinal Plants and Natural Products
Research Center, Hamadan University of Medical Sciences Hamadan, Iran
Abstract
Scrophularia striata from Scrophulariacea family has been used in Iranian folk medicine for the
treatment of infectious diseases. In this study we evaluated the synergistic effect of S. striata hydroalcoholic
extract (SSE) and commercially available antibiotics against Pseudomonas aeruginosa and Methicillin- resistant
Staphylococcus aureus (MRSA) bacteria. The resazurin-based microdilution method was used to determine the
minimum inhibitory concentration (MIC) values of plant extract and standard antibiotics. The interaction between
standard antibiotics and Scrophularia striata extract was evaluated by using the checkerboard method. The results
of this study revealed that SSE enhances the antibacterial activity of antibiotics. The combination of SSE and
Vancomycin had synergistic to additive effects against MRSA. SSE in combination with Gentamicin had
synergistic to additive effects against P. aeruginosa. The interaction between Ceftazidime and SSE was additive
against P. aeruginosa. The best result was the synergistic effect between SSE and Piperacillin-Tazobactam
against P. aeruginosa. In conclusion this research indicated that S. striata has the potential to enhance the
antibacterial activity of antibiotics and could be a source to the designing new compounds with synergistic effect
in combination with standard antibiotics.
Keywords: Scrophularia striata, Pseudomonas aeruginosa, Methicillin resistance Staphylococcus aureus, Synergy,
Antibiotics
Introduction
Antibiotic resistance has become a serious
public health problem worldwide (1) . Methicillin
resistant Staphylococcus aureus (MRSA) and
Pseudomonas aeruginosa are two of the more
problematic antibiotic- resistant pathogens
encountered over the past decade (2) .
MRSA infection is the main cause of nosocomial
infections and usually is associated with mortality,
morbidity and cost burden (3). Resistance to
methicillin has occurred in S. aureus by penicillin
binding protein mutation, a chromosomal
mutation(4) . The rate of MRSA infections is
increasing rapidly throughout the world and more
importantly, in the past decades the prevalence of
community acquired MRSA infections has notably
increased (5). The most common MRSA infections
are skin and subcutaneous tissue infections or
invasive infections such as meningitis, pneumonia,
osteomyelitis, lung abscess, bacteremia and
infective endocarditis (6). Several antibiotics
including Clindamycin, Co- trimoxazole,
Vancomycin and Daptomycin are being used to treat
MRSA infections (7) . However, the increasing
resistance of pathogens to these medicines and their
side effects have led to poor therapeutic outcomes
and increased mortality (8).
Pseudomonas aeruginosa is a gram negative
bacillus commonly found in soil, water and the
environment (9) . P. aeruginosa, as an opportunistic
pathogen is a major cause of hospital acquired
infections, especially in patients with underlying
conditions (10). P. aeruginosa has the ability to
survive on minimum nutritional necessities and to
tolerate different environmental conditions,
allowing this organism to persist in both hospital and
community setting(9). It has become difficult to
eradicate P. aeruginosa due to its high capacity to
resists antibiotics (11) . A number of antibacterial
agents such as Piperacillin-Tazobactam,
Ceftazidime, Cefepime, Ciprofloxacin and
Imipenem- Cilastatin are used to treat P. aeruginosa
infections but a limited number of these agents have
reliable activity against P. aeruginosa isolates (9).
Thus, it is necessary to find new ways to overcome
the resistance of MRSA and P. aeruginosa to
antibiotics. Combination therapy using two or more
1Corresponding author E-mail: ptamri@gmail.com
Received: 17/4/2021
Accepted: 20/6 /2021
Published Online First: 2021-12-11
Iraqi Journal of Pharmaceutical Science
https://doi.org/10.31351/vol30iss2pp219-224
mailto:ptamri@gmail.com
Iraqi J Pharm Sci, Vol.30(2) 2021 Synergistic effects of S. striata extract and antibiotics
220
antibacterial agents is an important strategy to
overcome antibiotic- resist organisms (12). However,
combining antibiotics result in more antibiotics
adverse effects and drug interactions.
Many previous studies have shown the
antibacterial activity of plant constituents and some
studies have proved the synergistic antibacterial
effect of the combination of antibiotics and
phytochemicals (13, 14, 15) .
Scrophularia striata (Scrophulariaceae) is an
herbaceous plant that grows wild in the west regions
of Iran (16). In traditional medicine, it has been used
for the treatment of the inflammatory and infectious
diseases (17) . Several studies have shown biologic
activities of S. striata, including antibacterial (18),
anti-inflammatory (19), antioxidant (20), anticancer (21)
and healing effects (22).
The aim of this study was to investigate the
synergistic effect between SSE and commonly used
antibiotics against MRSA and P. aeruginosa.
Materials and Methods
Materials and Strains
Nutrient Agar (NA) and Muller Hinton
Broth (MHB) culture media were obtained from
Merck (Darmstadt, Germany) and used for growing
the bacteria and antibacterial activity tests
throughout the study.
Standard strains of MRSA (ATCC 33591) and P.
aeruginosa (ATCC 27853) were obtained from
Persian Type Culture Collection in Iranian Research
Organization for Science and Technology (IROST),
Tehran, Iran. Isolates were maintained in Tryptic
Soy Broth (TSB) containing 15% glycerol at -80 ° C
until use. Bacterial inocula were prepared from 24 h
culture of the organisms grown on nutrient agar
(NA) plates. The organisms were harvested, and
suspended in normal saline (NS) to produce a
MacFarland 0.5 (turbidity equivalent to 108 colony
forming units (CFU) (23).
Preparation of S. striata Extract
The aerial parts of S. striata were collected
from the west parts of Iran (Ilam province). The
authentication of herb material was performed at the
Department of Pharmacognosy, School of
Pharmacy, Hamadan University of Medical
Sciences. The plant was dried and grounded to a
fine powder. The plant hydroalcoholic
(ethanol/distilled water 7/3 v/v) extract was
prepared by using maceration method (24) .
Preparation of stock and standard solutions
A SSE stock solution of 32mg/ml was
prepared by accurately weighing and dissolving the
extract in sterile dimethyl sulfoxide (DMSO).
Aliquots of the stock solution were brought to 10 ml
volume using sterile 0.9% (w/v) normal saline to
obtain further dilutions.
Commercial parenteral dosage forms of antibiotics
[Co-trimoxazole (CTX), Clindamycin (CLD)
Vancomycin (VAN), piperacillin + Tazobctam
(PIP-Tazo), Gentamicin (GEN) and Ceftazidime
(CEF)] were used for preparing antibiotic solutions.
Whole content of one vial or ampule was dissolved
and further diluted in normal saline to obtain
antibiotic solution with the intended concentration
Determination of Minimum Inhibitory
Concentration (MIC)
MIC of S. striata extract against MRSA
and P. aeruginosa were determined on sterile 96
well microdilution plates according to the Clinical
and Laboratory Standards Institute (CLSI)
Guidelines (25). SSE solutions in the range of
concentrations of 32 - 0.015 mg/ml were prepared
through two-fold serial dilution of the stock
solution. 100 µl of each solution was mixed with 100
µl of Mueller Hinton Broth (MHB) medium
inoculated by bacterial suspension (containing 106
CFU/ml) in three wells row of microdilution plate.
Four wells without adding the extract were used to
show maximum growth for each microorganism and
four others containing uninoculated medium were
used as negative control to show the aseptic
technique.
MIC of the antibiotics against corresponding
microorganisms were determined using the same
method explained above.
After incubation of the plates at 37° C for 24 h, the
lowest concentration at which no growth was
observed was determined as MIC (26). Visual
inspection was used to determine any signs of
bacterial growth and turbidity. For more accurate
determination of MIC, 50 µl of 0.002% w/v sodium
resazurin solution was added to the wells and color
change was investigated after 1 h incubation at 37
°C. Change of color from blue to purple or red was
considered as a sign of bacterial growth (27). The test
was performed in three separate experiments, each
one in three replicates. Quantities determined as
MIC in at least two experiments were reported as the
final MIC.
Determination of Minimum Bactericidal
Concentration (MBC)
MBC was determined by transferring 100
µl culture from the wells exhibited no growth on NA
plates and incubated at 37° C for 24 h. The lowest
concentrations of SSE and antibiotics that show no
colony growth on NA were reported as MBC. This
test was repeated in three separate experiments.
Quantities determined as MBC in at least two tests
were reported as the final MBC.
Investigation of Antibacterial Activity of
combined S. striata Extract and Antibiotics
The antibacterial activity of combined
SSE and antibiotics was investigated using the
checkerboard dilution test that is one of the methods
used for evaluation of in vitro synergy for multiple
drugs (28). This test determines the impact on
antibacterial activity of the combination of
Iraqi J Pharm Sci, Vol.30(2) 2021 Synergistic effects of S. striata extract and antibiotics
221
antibacterial agents in comparison to their individual
activities. Fractional Inhibitory Concentration (FIC)
index value was used to evaluate the interaction of
the two agents tested. FIC is determined according
to the following equation (Eq. 1), where A and B are
the MIC for each antibacterial agent when combined
in a single well, and MICA and MICB are the MIC
for each agent individually.
FIC Index = FICA+FICB= A/MICA + B/MICB
FIC Index values are interpreted as follows: FIC
Index ≤ 0.5, synergistic, 0.5 ≤ FIC Index ≤ 1,
synergistic to additive, 1 ≤ FIC Index ≤ 4, additive,
and FIC Index ≥ 4, antagonistic(29).
Checkerboard test was performed for combinations
of the SSE with CTX, CLD and VAN against
MRSA and with PIP-Tazo, GEN and CEF against P.
aeruginosa. An 8-by-8 well configuration on sterile
96 well microdilution plates was utilized. Final
concentrations of the SSE and antibiotics in the
wells ranged from 1/8 × MIC to 4 × MIC. The wells
contained MHB medium inoculated with 106
CFU/ml of the respective microorganism. Positive
and negative controls containing inoculated and
uninoculated MHB were set on every plate. After
incubation of the plates at 37° C for 24 h, bacterial
growth was investigated by visual inspection
followed by adding 50 µl resazurin solution to
observe the color change. The lowest FIC index of
all the non-turbid wells along the turbidity/non-
turbidity interface was used for interpretation of
the results. This test was performed in triplicate and
results observed in at least two replicates were
reported.
Statistical Analysis
Microsoft Excel 2016 was used to calculate
mean and variance of data.
Results
Antibacterial Activity
The results of the evaluation of the
antibacterial activity of SSE showed that this extract
has low activity against MRSA (MIC=8 mg/ml)
(Figure. 1) and P. aeruginosa (MIC= 4 mg/ml,
MBC= 8mg/ml) (Figure 2).
The SSE had no bactericidal activity against MRSA
at the concentrations of 32-0.015 mg/ml. The
MRSA strain was resistant to Clindamycin and Co-
trimoxazole. The MIC and MBC of SSE and
standard antibiotics are shown in Table.1.
Figure. 1. Determination of MIC for Vancomycin and Scrophularia striata against methicillin resistance
Staphylococcus aureus (ATCC 33591).
Figure. 2. Determination of MIC for Ceftazidime and Gentamicin against P. aeruginosa (ATCC 27853)
Iraqi J Pharm Sci, Vol.30(2) 2021 Synergistic effects of S. striata extract and antibiotics
222
Table 1. The antibacterial activity of antibiotics and S. striata extract
MRSA P. aeruginosa
SSE CTX CLD VAN SSE PIP GEN CEF
Concentrations 0.015-
32
mg/ml
0.25-
2000
µg/ml
0.015-256
µg/ml
0.031-64
µg/ml
0.015-
32
mg/ml
0.031-64
µg/ml
0.031-
64
µg/ml
0.031-64
µg/ml
MIC 8
mg/ml
ND* ND 2 µg/ml 4 mg/ml 2 µg/ml 0.25
µg/ml
0.062
µg/ml
MBC ND ND ND ND 8 mg/ml ND 1 µg/ml 0.5
µg/ml
* Not determined in the concentration ranges
Study of Synergistic Effect between Antibiotics and
SSE
The results of interaction between SSE and
antibiotics expressed in FICI are shown in Table. 2.
The combination of SSE and Vancomycin had
synergistic to additive effect against MRSA. The
combinations of SSE and Pip + Tazo showed
synergism against P. aeruginosa and in the case of
the combination of SSE and Gentamicin the
interaction was synergism to additive. The
interaction between SSE and Ceftazidime was
additive (Figure 3). The combination of SSE and
Pip-Tazo showed the best synergistic capacity
against P. aeruginosa.
Table 2. The interaction between antibiotics and S. striata extract
Bacteria Antibiotics + SSE FICI Interpretation
MRSA VAN 0.75 synergistic to additive
P. aeruginosa
PIP 0.3 synergism
GEN 0.75 synergistic to additive
CEF 1.5 additive
Figure 3. Checkerboard test for determination of combined antibacterial activity of Gentamicin and
Scrophularia. striata extract against P. aeruginosa (ATCC 27853), a) after incubation, b) after adding the
resazurin solution and c) after incubation of resazurin
Discussion
As the results of this study showed, the SSE
in combination with standard antibiotics has good
synergistic and additive effects and has the potential
to be used as an adjunct therapy in the treatment of
infections caused by resistant microorganisms such
as P. aeruginosa and MRSA. The mechanism of
SSE to enhance the antibacterial activity of
antibiotics is unknown. In addition to the direct
antibacterial activity of plants, one of the possible
mechanisms for the synergistic antibacterial effect
of plants extract and antibiotics is the modifying and
inhibiting the acquired resistance in bacterial cell
and thus enhance the antibiotic antibacterial activity
(13).
The main compounds that isolated and characterized
from SSE were flavonoids such as quercetin,
nepitrin and isorhamnetin-3-O-rutinoside (30).
Flavonoids may affect cellular membrane, inhibit
nucleic acid synthesis, and energy metabolism.
Iraqi J Pharm Sci, Vol.30(2) 2021 Synergistic effects of S. striata extract and antibiotics
223
Additionally, flavonoids may interrupt cell
membrane and cell wall synthesis (31). According to
the results of this study the SSE has better
antibacterial activity against P. aeruginosa (MIC= 4
mg/ml) comparing to MRSA (MIC= 8 mg/ml) and
in combination with Pip- tazobactam has a
synergistic effect against P. aeruginosa. In addition,
SSE enhanced the Gentamicin antibacterial activity
against this microorganism. The resistance of P.
aeruginosa against antibiotics may be intrinsic,
acquired or adaptive. This microorganism has a low
permeable outer membrane, expresses an efflux
pump and produces antibiotic-inactivating enzymes
to resist antibiotics, intrinsically. The acquired
resistance of this organism may be due to mutation
changes or horizontal gene transfer. Previous studies
indicated that the phenolic compounds and
flavonoids initially change the permeability of cell
membrane and this leads to the leaking of cellular
content or disrupt the membrane structure by
interfering with membrane proteins (32, 33).
Therefore, SSE may increase the entry of antibiotics
into bacterial cells by increasing the permeability of
bacterial cell membrane.
SSE also enhanced the Vancomycin antibacterial
activity against MRSA. Vancomycin is a
bactericidal antibiotic that inhibits bacterial cell wall
synthesis by binding to D- Ala-D-Ala peptide and
following that preventing peptidoglycan cross-
Linking by transpeptidation and eventually inhibit
the cell wall biosynthesis and bacterial cell death (34).
Vancomycin has been widely used for the treatment
of MRSA infections and it has led to the emergence
of Vancomycin resistant S. aureus (35). The
augmentation of antibacterial activity of
Vancomycin by SSE could be a result of SSE
antibacterial activity or modifying the mechanism of
acquired resistance.
Conclusion
In conclusion, our findings in this study
revealed the synergistic and additive activity of SSE
combined with standard antibiotics against
P.aeruginosa and MRSA. Antibiotics resistance is a
growing problem and the perspective of antibiotics
effectiveness in the future is uncertain. Plants are
important sources of biologically active compounds
with antibacterial activity. The antibacterial effect of
plants can be due to their direct activity against
bacteria or their synergistic activity with antibiotics.
S. striata could be a source of new antibacterial
compounds. However, the further studies are needed
to explore the mechanism underlying its synergistic
effects. In addition, the toxicity, antibacterial
activity and bioavailability of the SSE should be
studied in vivo.
Conflict of Interest
The authors declare there is no conflict of
interest.
Acknowledgement
The study was funded by Vice-chancellor
for Research and Technology, Hamadan University
of Medical Sciences under Grant (number:
980127289).
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