Synergistic Antibacterial Activities of Bioactive Compounds
from Streptomyces sp. RS2 in Combination with
Vancomycin against Staphylococcus aureus
Nongyao Nonpanya and Suwanna Niamsanit
Department of Microbiology, Faculty of Science, Khon Kaen
University, Khon Kaen 40002, Thailand
nongyaononpanya@gmail.com
Lumyai Wonglakorn
Clinical Microbiology Laboratory, Srinagarind Hospital,
Faculty of Medicine, Khon Kaen University, Khon Kaen
40002, Thailand
Abstract - Two bioactive compounds, namely tetrangulol methyl
ether (1) and 2-phenylacetamide (2) were produced by Streptomyces sp.
RS2, and were also effective against Staphylococcus aureus and
Methicillin-resistant S. aureus (MRSA). The objective of this research
was to determine synergistic antibacterial combinations between the
active compounds with an antibiotic against S. aureus. The combined
effects analysis was performed by the checkerboard method to
determine the Fractional Inhibitory Concentration (FIC) indexes, and
all synergistic combinations were confirmed using time kill kinetic
analysis. Synergistic effects were observed when compound 1 and 2 were
combined with vancomycin (VA) against S. aureus ATCC 25923. FIC
indexes of compounds 1+VA, 2+VA and 1+2 combinations were 0.313,
0.500 and 0.375, respectively. The result of time-kill kinetic analysis
showed that the compounds 1, 2 and VA, and compound combinations
1+VA, 2+VA and 1+2 exhibited synergistic activity against S. aureus
ATCC 25923 within 4, 6 and 24 h. In addition, the effects of the active
compounds on the tested S. aureus and MRSA were observed by
Scanning Electron Microscopy (SEM). The results illustrate that
bacterial cells were slightly changed and decreased after incubation with
the compounds 1 and 2 and the 1+2 combination. These results
demonstrate that the active compound exhibited synergistic activity
against S. aureus ATCC 25923, and the two active compounds will be
studied particularly for the role or function of the two bioactive
compounds in the future.
Index Terms - Synergistic Activity, Bioactive Compounds,
Anti-S. aureus Activity, Streptomyces sp. RS2
I. INTRODUCTION
The wide use of antimicrobial compounds, mostly antibiotics, in
the treatment and prevention of bacterial infections, in the food
industry and in agriculture has led to the emergence and spread of
drug and multidrug resistant (MDR) bacteria [1]. MDR bacteria are
pathogens that resist treatment with more than one antibiotic which
are often extremely difficult or impossible to kill and more expensive
to treat [2]. The epidemiology of MDR bacteria is the main
public health problem in hospitals or other health care
facilities that can cause nosocomial or healthcare associated
infections, namely ventilator-associated pneumonia, catheter-
Kwanjai Kanokmedhakul and Jakkapat Paluka
Natural Products Research Unit, Department of Chemistry,
and Center for Innovation in Chemistry, Faculty of Science,
Khon Kaen University, Khon Kaen 40002, Thailand
kwanjai@kku.ac.th
Nattadon Pannucharoenwong and Snunkhaem Echaroj
Department of Mechanical Engineering, Faculty of
Engineering, Thammasat University, 12120, Thailand
pnattado@engr.tu.ac.th
related bloodstream infections and catheter-associated urinary
tract infections [1, 3, 4]. Methicillin-resistant Staphylococcus
aureus (MRSA), as the multidrug-resistant Gram-positive
bacteria, is one of the most important pathogens which are spread
all over the world, and it can cause the Staphylococcal scalded
skin syndrome [5, 6]. Therefore, novel antimicrobial compounds and
broad-spectrum activity of the active compounds against MDR
bacteria are needed. Natural sources of biologically active compounds
are animals, plants, fungi and bacteria, mainly Actinomycetes [7, 8].
Actinomycetes, especially the genus Streptomyces, play an important
role in the production of bioactive compounds such as antibiotics,
antimicrobials, anticancer, antitumor, immunosuppressive agents and
enzymes [9, 10]. The medically important antibiotics such as
streptomycin, erythromycin, neomycin, daptomycin, natamycin and
tetracycline are produced by genus Streptomyces [11, 12, 13]. Many
researchers have studied the synergistic activity resulting from the
combination of bioactive compounds with antibiotics
experimentally [14]. The results of these experiments show that
even drugs only active against Gram-positive bacteria, such as
vancomycin, may have antibacterial activity against Gram-
negative bacteria, when combined with two or more antibiotics.
The checkerboard method and time-kill kinetic analysis are usually
used to assess drug-drug combinations [15]. Many reports have
suggested that the use of bioactive compounds and drug
combinations can potentially prevent the growth of MDR
pathogens, increase antimicrobial efficacy and provide broader
spectrum antimicrobial activity than antibiotic monotherapy [16].
Therefore, the objective of this research was to determine the
synergistic effects of the bioactive compounds produced by
Streptomyces sp. RS2, in combination with an antibiotic, against S.
aureus and MRSA. In addition, the effects of the active
compounds on the tested pathogenic bacteria were observed by
scanning electron microscopy (SEM).
II. MATERIALS AND METHODS
A. Streptomyces sp. RS2, Test Pathogens and Growth Conditions
 The strain RS2 was previously isolated and cultured on
international Streptomyces project (ISP) medium no. 2 and
incubated at 30°C for 7 days [17]. Pathogenic bacteria were S.
aureus ATCC 25923, clinical strains of S. aureus and methicillin-
resistant S. aureus (MRSA) were obtained from Srinagarind
Hospital Laboratory Unit, Faculty of Medicine, Khon Kaen
University, Khon Kaen, Thailand. The bacterial strains were
cultured onto Mueller-Hinton agar (MHA) and incubated at 37°C
for 18-24 h. Purified colonies (4-6 colonies) were selected and
inoculated into Mueller-Hinton broth (MHB) to turbidity
comparable to that of 0.5 McFarland standards, which is
equivalent to a bacterial count of approximately 108 CFU/ml.
B. Bioactive Compounds
The cultured medium of the Streptomyces sp. RS2 was
extracted incessantly at room temperature with increasing
polarity of the organic solvents ethyl acetate (EtOAc) and
methanol (MeOH). Crude extracts were purified by silica gel
flash column chromatography and recrystallized, using
Sephadex LH-20 and preparative thin-layer chromatography.
Compounds 1 and 2 were separated from the crude EtOAc and
MeOH extracts, respectively. Based on physiochemical and
spectral data, compound 1 (6 mg, Rf 0.39, brown solid) and
compound 2 (4 mg, Rf 0.58, white solid) were identified as
tetrangulol methyl ether and 2-phenylacetamide, respectively.
C. Minimum Inhibitory Concentration (MIC) Determination
The MIC values of the active compounds were determined
using a broth micro-dilution method according to Clinical and
Laboratory Standards Institute (CLSI) guidelines [18]. Serial 2-
fold dilutions of the active compounds 1 and 2 with final
concentrations of 128 to 0.25 μg/ml were prepared with 50 μl of
MHB in 96-well microtiter plates, after that 50 μl of S. aureus
ATCC 25923 inoculum suspension (5×105 CFU/ml) was added to
each well. Vancomycin was used as positive control. The tested
microtiter plates were incubated at 37°C for 18-24 h. After
incubation, 10 µl of 0.18% resazurin solution was subjected to the
tested plates and incubated at 37°C for 2-3 h. The lowest
concentration of the compounds 1 and 2 that inhibited growth
(blue or purple color) was recorded as MIC values, while a pink
color indicated bacterial growth as negative result [19].
D. Synergistic Antibacterial Effect of Bioactive Compounds
The combined effects of the active compounds 1, 2 and
vancomycin (VA) were evaluated by agar well diffusion and
checkerboard methods to obtain the fractional inhibitory
concentration (FIC) index [16, 20, 21]. The active compounds
1, 2 and VA with final concentrations of 30 µg/well were
prepared and synergistic activity against S. aureus ATCC
25923 determined using the agar well diffusion method as
described by Lorian [22]. Additionally, compounds 1, 2 and VA in
solutions with various concentrations of 0.125MIC to 4MIC were
prepared and tested for antibacterial interaction. Fifty μl of
inoculum suspension of S. aureus ATCC 25923 (5 ×105 CFU/ml)
was added to each well, and the tested plates were incubated at
37°C for 18-24 h. The results of compounds 1, 2 and VA
combinations had their antibacterial activities against S. aureus
ATCC 25923 measured by determining the FIC index, which was
calculated from the following formula,
(1)/(MIC1) + (2)/(MIC2) = FIC 1 + FIC 2 = FICI
where FIC 1 is the MIC of the combination/MIC of compound
1 alone, and FIC 2 is the MIC of the combination/MIC of
compound 2 alone. The FICI is the FIC index, and its value was
interpreted as follows: ≤ 0.5 (synergism), 1 (additive), 1–4
(indifferent) and >4 (antagonism) [21, 22].
E. Time‑Kill Assays
Time-kill kinetics test was used to investigate the best time for
the active compound that kills the bacterial cells. In this assay,
compounds 1 and 2 with concentrations of 0.5MIC to 4MIC were
prepared and inoculated with 50 μl of inoculum suspension (5
×105 CFU/ml), and then incubated at 37°C. At several time points
(0, 1, 2, 4, 6, 8, 12 and 24 h), the tested bacteria S. aureus ATCC
25923 was serially diluted and the number of colony-forming units
per milliliter (CFU/ml) measured by the drop plate method on
MHA medium. The numbers of CFU/ml were converted to log10
values. The result was measured in triplicate and compared with
the growth control [22, 23].
F. Morphological Changes Observed by Scanning Electron
Microscopy (SEM)
S. aureus ATCC 25923 and MRSA were treated with the
compounds 1, 2 and VA at various concentrations (1MIC, 2MIC)
and incubated at 37oC for 18-24 h. Bacteria cells treated with
sterile water was used as a control. After incubation, the tested
bacteria were fixed in 2.5% glutaraldehyde solutions at 4oC for 3 h
and dehydrated in a graded series being 30%, 50%, 60%, 70%, 90
and twice with 100% ethanol solutions. Bacteria cells were
critical-point dried, mounted on stubs, sputter-coated with gold
and finally observed by SEM (LEO 1450vp) at the Department of
Biology, Faculty of Science, Khon Kaen University, Khon Kaen,
Thailand [24, 25].
III. RESULTS AND DISCUSSION
A. Synergistic Activities of Bioactive Compounds
The MIC values of compounds 1, 2 and VA against S.
aureus ATCC 25923 were 1, 16 and 0.5 µg/ml, respectively.
Additionally, the synergy was evaluated using agar well
diffusion and the checkerboard method, with fractional inhibitory
concentration index (FICI) between compounds 1, 2 and VA. The
results of the agar well diffusion method show that compounds 1, 2
and VA exhibited synergistic activity against S. aureus ATCC
25923 as shown in Fig. 1. The FICI values of compound
combinations 1+VA, 2+VA and 1+2 were 0.313, 0.500 and
0.375, respectively (Table 1). The results show that all of these
combinations had FIC values less than 0.5, which indicates
synergistic activity against S. aureus ATCC 25923. The synergistic
activities were observed in the active compound combinations, and
an antagonistic activity was not observed.
Streptomyces sp. RS2, accession number MF 094448.1, was
isolated from a soil sample, and it was identified as genus
Streptomyces. As previously reported, Streptomyces sp. RS2 is an show the numbers of surviving S. aureus ATCC 25923 rapidly
antibacterial producing strain that exhibits activity against both decreased after incubation for 4, 6 and 24 h (Fig. 4). The numbers
Gram-positive and Gram-negative bacteria [17]. Al-Hulu et al. of surviving bacteria after testing with the combinations of
[26] reported that S. gelaticus strain SAM10 exhibited activity compounds 1+2, 1+VA and 2+VA were 3.09, 2.26 and 2.64 log10
against S. aureus, Pseudomonas aeruginosa and Escherichia coli. CFU/ml after incubation for 6 h, respectively.
Kuntsmann and Mitscher [27] and Abdelfattah et al. [28] showed
that a bioactive compound, namely tetrangulol methyl ether, was
obtained from Actinomyces sp. and Streptomyces sp. This
compound exhibited antimicrobial activity against Bacillus
subtilis, E. coli, S. viridochromogenes and S. aureus [28]. Choi et
al. [29] reported that the tetrangulol methyl ether was a quinine
reductase (QR) inhibitor which may have anti-malarial, anti-tumor
and chemoprevention activity. Odumosu et al. [30] presented that
16 secondary metabolites such as kanamycin, indolyl-3-carboxylic
acid, streptomycin and gentamicin as well as benzeneacetamide
were found in the crude EtOAc extracts of S. coelicolor strain
AOB KF 977550 that exhibited broad spectrum activities against
MRSA, B. coagulans UL 001, and E. coli as well as the standard Fig. 2 Antibacterial activity against S. aureus ATCC 25923 of compound 1 observed
isolates of Klebsiella pneumonia ATCC 8308, Gardnerella by time-kill determination at concentrations of 0.5xMIC, 1xMIC, 2xMIC and 4xMIC;
vaginalis ATCC 27853 and Salmonella typhi ATCC 13311. control, S. aureus growth; 1, compound 1 and VA, vancomycin

Fig. 1 Synergistic activity of compounds 1+VA (A), 2+VA (B) and 1+2 (C)
against S. aureus ATCC 25923 by the agar well diffusion method

TABLE I Fig. 3 Antibacterial activity against S. aureus ATCC 2592 of compound 2 observed by
SUSCEPTIBILITY OF S. AUREUS ATCC 25923 TO COMBINATIONS OF time-kill determination at concentrations of 0.5xMIC, 1xMIC, 2xMIC and 4xMIC;
COMPOUNDS 1, 2 AND VA control, S. aureus growth; 2, compound 2 and VA, vancomycin
Com. MIC MICa FIC FICIb In.
x y MICx MICy MICx MICy FICx FICy
(µg/ml) (µg/ml) (µg/ml) (µg/ml)
1 VA 1 0.5 0.0625 0.125 0.0625 0.25 0.313 Syn

2 VA 16 0.5 4 0.125 0.25 0.25 0.500 Syn

1 2 1 16 0.125 4 0.125 0.25 0.375 Syn

Com., compounds; 1, compound 1; 2, compound 2; VA, vancomycin; FIC,

fractional inhibitory concentration; FICI, fractional inhibitory concentration index;
Syn, synergistic activity; x, compound x and y, compound y; In., interactions
a Combinations of compounds 1, 2 and VA giving the lowest FICI.
b FICI = sum of the FIC of the two compounds in combination

B. Synergistic Activities of Bioactive Compounds

The time-kill curves (TKC) of the active compounds 1, 2 alone
and combined with vacomycin exhibited activity against S. aureus
ATCC 25923. The results show that the number of surviving
S. aureus ATCC 25923 at 0.5xMIC, 1×MIC, 2×MIC and 4×MIC
concentrations of compound 1 were 4.97, 3.49, 3.21 and 2.45 log10
CFU/ml after incubation for 4 h (Fig. 2), and of compound 2 were
4.98, 4.27, 3.61 and 3.07 log10 CFU/ml after incubation for 6 h
(Fig. 3), respectively. The TKC studies of the active compounds
and VA combinations showed synergistic activity that exhibited
bactericidal action against S. aureus ATCC 25923. The results
Fig. 4 Synergistic activity against S. aureus ATCC 25923 of compounds 1
(1xMIC), 2 (1xMIC) and combined with VA (0.5xMIC) observed
by time-kill determination; control, S. aureus growth; 1,
compound 1; 2, compound 2 and VA, vancomycin
According to antibiotic susceptibility testing, a similar result
was reported by Jang et al. [31], that the MIC and MBC values
of baicalein were ranging from 80-320 and 160-640 µg/ml
against oral bacteria such as Streptococcus mutans ATCC
25175, S. sanguinis ATCC 10556 and S. sobrinus ATCC 27607.
The combination effects of baicalein with antibiotics were
synergistic (FIC index <0.375-0.5). In addition, the time-kill
assay showed that the growth of the tested bacteria was
destroyed after 1-6 h. Chawawisit et al. [32] showed MIC and
FIC values of 2,4-Di-tert-butylphenol and vancomycin
determined by broth microdilution and checkerboard methods,
respectively. The MIC values were in the ranges of 15.63-62.50
and 1.56-3.12 µg/ml, respectively. The combination of 2,4-Di-
tert-butylphenol with vancomycin was partially synergistically
active against 5 clinical strains of MRSA which were classified
as marcrolide lincosamide streptogramin group B resistance.
Additionally, Chan et al. [33] showed that the combination of
chloramphenicol and ibuprofen/aspirin was synergistic against
reference MRSA, and displayed a synergistic activity against
MRSA isolates.
C. Effect of the Active Compounds on Bacterial Cells
Cell morphology of S. aureus ATCC 25923 and MRSA
were slightly changed and decreased after treatment with
compounds 1 (Fig. 5 B and F), 2 (Fig. 5 C and G) and 1+2
(Fig. 5 D and H) combinations at the 1xMIC concentration
after 18 h of incubation. The results suggest that these
active compounds could be affecting cell morphology and
destroyed the tested S. aureus ATCC 25923 and MRSA,
while the number of pathogens was decreased after 18 h of
incubation (Fig. 5).
Fig. 5 SEM micrograph of S. aureus ATCC 25923 (A-D) and MRSA (E-H)
after incubation for 18 h without any treatment used as the control (A and E),
after treating with compound 1 (B and F), compound 2 (C and G) and
compounds 1+2 combination (D and H). Bar represents 200 nm
IV. CONCLUSION
Streptomyces sp. RS2, accession number MF 094448.1,
was identified as genus Streptomyces. This study reports that
Streptomyces sp. strain RS2 exhibits broad-spectrum activity,
and this strain was cultured, extracted, purified and the
antibacterial activity of Streptomyces-derived compounds
evaluated against S. aureus and MRSA strains. Interestingly,
tetrangulol methyl ether and 2-phenylacetamide exhibited
broad spectrum antimicrobial activity against Gram-positive
and Gram-negative bacteria. 2-phenylacetamide has usually
been used in the production of penicillin G, while tetrangulol
methyl ether has been used as a quinine reductase (QR)
inhibitor. From the results of antimicrobial susceptibility assay
and TKC studies, compounds 1, 2 and VA combinations
exhibited antibacterial activity against S. aureus ATCC 25923,
and the numbers of the tested bacteria were decreased after
treatment with these compounds. Therefore, this study
reported that the use of tetrangulol methyl ether, 2-
phenylacetamide and vancomycin combinations exhibited
synergistic activity, and these compounds will be studied
concerning the mechanisms or function of the active
compounds in the future.
ACKNOWLEDGMENT
We are also thankful to the Department of Biology,
Chemistry and Microbiology, Faculty of Science, Khon Kaen
University, for the support of facilities. This project was
supported by the human resource development in science project
(Science Achievement Scholarship of Thailand, SAST).
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