Bioresource Technology 218 (2016) 1266–1270

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Bioresource Technology
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Short Communication

Production of a new tetracyclic triterpene sulfate metabolite sambacide

by solid-state cultivated Fusarium sambucinum B10.2 using potato as
substrate
Jian-Wei Dong 1, Le Cai 1, Xue-Jiao Li, Rong-Ting Duan, Yan Shu, Feng-Yun Chen, Jia-Peng Wang,
Hao Zhou, Zhong-Tao Ding ⇑
School of Chemical Science and Technology, Yunnan University, Kunming 650091, China

h i g h l i g h t s g r a p h i c a l a b s t r a c t

 A new triterpene sulfate sambacide

(1) was produced by SSF with F.
sambucinum.
 Sambacide showed significant
antibacterial activities against S.
aureus and E. coli.
 The fermentation conditions were
optimized.
 Sambacide could be produced with a
high yield of 19.04 ± 0.82 g/kg dw.

a r t i c l e i n f o a b s t r a c t

Article history: The aim of this work is to explore integracide analogues from secondary metabolites of microorganisms.
Received 30 May 2016 A new tetracyclic triterpene sulfate was produced by solid-state fermentation (SSF) with Fusarium sam-
Received in revised form 2 July 2016 bucinum B10.2. The tetracyclic triterpene sulfate was identified as (3S,5R,10S,11S,12S,13R,17R,20R)-4,4-
Accepted 4 July 2016
dimethylergosta-8,14,24-triene-3,11,12-triol-12-acetate, 3-sulfate on the basis of HRESIMS, NMR and
Available online 5 July 2016
electronic circular dichroism (ECD) spectra and named sambacide (1). The antibacterial and antifungal
assays of sambacide (1) showed significant antibacterial activities against Staphylococcus aureus and
Keywords:
Escherichia coli. The fermentation conditions including culture media, fermentation temperature and
Sambacide
Solid-state fermentation
time, were optimized. And potato was selected as the fermentation substrate, 28 °C was used as the fer-
Fusarium sambucinum mentation temperature, and 20-days fermentation time was determined for F. sambucinum-SSF to pro-
Antibacterial activity duce sambacide (1) with a high yield of 19.04 ± 0.82 g/kg. This paper provides an efficient approach to
Antifungal activity produce the antibacterial and antifungal agent sambacide (1) in a very high yield.
Ó 2016 Elsevier Ltd. All rights reserved.

1. Introduction antibacterial and antifungal activities (Singh et al., 2003a), and

Integracides, a class of a 4,4-dimethylergostane derivatives, are
moderately potent and selective inhibitors of HIV-1 integrase
(Singh et al., 2003a), and exhibit various bioactivities including
⇑ Corresponding author.
E-mail address: ztding@ynu.edu.cn (Z.-T. Ding).
1
The first two authors contributed equally to this paper.
cytotoxic activity (Ibrahim et al., 2016b). The structure-activity
relationship research of HIV-1 integrase inhibitor revealed that 3-
sulfate esters of the related natural product of integracides exhibit
several folds activity than original compounds (Singh et al., 2003a).
Triterpene sulfates (e.g. integracides) had been reported as poten-
tial phytotoxic metabolites from several Fusarium species
(Burmeister and Vesonder, 1990). Hence, searching the inte-

http://dx.doi.org/10.1016/j.biortech.2016.07.014
0960-8524/Ó 2016 Elsevier Ltd. All rights reserved.
 J.-W. Dong et al. / Bioresource Technology 218 (2016) 1266–1270
gracides and related compounds from Fusarium spp. has attracted
our attention.
Solid-state and submerged fermentation (SSF and SmF) are two
types of fermentation patterns for further exploring the second-
metabolites of fungi. Although, SmF has various advances, e.g.
short fermentation time, however, some metabolites could not be
produced by SmF (Li et al., 2015b). SSF is a class of the fermenta-
tion process, in which microbes grow on solid materials generated
from agricultural/horticultural residues without the presence of
free liquid (Azabou et al., 2016; Bhargav et al., 2008). SSF is an effi-
cient fermentation holding a series of advantage, such as producing
some complex structure metabolites because of its longer meta-
bolic circle. The bioprocess of SSF doesn’t need an excess of free
water, and it offers potential benefits for microbial cultivation for
bioprocesses and product development (Nalini and Parthasarathi,
2014; Yong et al., 2011).
This paper aims to explore the integracides analogues from the
metabolites of Fusarium spp. through both SmF and SSF. A new
integracides analogue, (3S,5R,10S,11S,12S,13R,17R,20R)-4,4-dime
thylergosta-8,14,24-triene-3,11,12-triol-12-acetate, 3-sulfate
named sambacide (1), with antibacterial and antifungal activities,
was produced by solid-state cultivated Fusarium sambucinum
B10.2. The fermentation conditions were optimized on aspects of
culture medium, fermentation temperature and time.
2. Materials and methods
2.1. Microorganism and the seed cultivation conditions
F. sambucinum B10.2 was obtained from the Yunnan Institute of
Microbiology, Yunnan University, Kunming, China. The nucleotide
sequence data reported in this paper were deposited at GenBank
(accession number: KU987439).
Potato dextrose agar (PDA; 1 L of water, 200 g of potato, 20 g of
dextrose, and 15 g of agar, natural pH) slant culture medium was
inoculated with the aforementioned fungus and incubated in a
constant-temperature incubator at 28 °C for 5 days. A 500-mL con-
ical flask containing 200-mL potato dextrose broth (PDB; 1 L of
water, 200 g of potato, and 20 g of dextrose, natural pH) was used
as seed culture medium. The proper mature slants were added to
the seed culture medium and placed on a rotary shaker shaking
at 140 r/min at 28 °C for 3 days.
2.2. Submerged fermentation (SmF)
A 500-mL conical flask containing 200-mL PDB was selected as
the SmF culture medium. After sterilizing at 121 °C for 30 min, the
20-mL seed cultures were added and the medium was incubated
on a rotary shaker shaking at 140 r/min at 28 °C for 7 days.
2.3. Solid-state fermentation (SSF)
A 50 g of potato was added to a 350-mL glass spawn bottle as
the SSF culture medium. After this fermentation culture medium
was sterilized at 121 °C for 30 min, the 10-mL seed cultures were
added and the medium was incubated in a constant-temperature
incubator at 28 °C for 30 days.
2.4. Extraction and isolation
After 30-days SSF, the medium was percolated with methanol
for 12 h. The removal of the solvent in vacuum afforded the crude
extract (8.5 g). The extract was further chromatographed over sil-
ica gel column chromatography (CC) eluting with chloroform–
1267
methanol (20:1–5:1), then purified by Sephadex LH-20 (methanol)
and yielded 1 (30 mg).
2.5. Effects of culture media
Potato, rice bran, wheat bran, and corn flour selected as culture
media were added to 350-mL glass spawn bottles, respectively and
sterilized at 121 °C for 30 min. After the seed cultures were added,
the medium was incubated at 28 °C for 30 days.
2.6. Effects of fermentation time
Potato was selected as the substrate. Fermentation using the
method described in Section 2.3. The yields were determined by
HPLC (detailed information, see Supplementary Data) after 5 days,
10 days, 20 days, 30 days and 40 days fermentation, respectively.
2.7. Effects of fermentation temperature
Effects of fermentation temperature were measured using the
fermentation method described in Section 2.3. The fermentation
temperatures were set to 20 °C, 28 °C, 37 °C, and ambient temper-
ature (AT, 8–20 °C). The contents were determined by HPLC analy-
sis described in Supplementary Data.
2.8. Antibacterial and antifungal activities
Antibacterial and antifungal activities were performed in 96-
well sterilized microplates using a previous microdilution method
(Dong et al., 2015). All experiments were repeated thrice.
3. Results and discussion
3.1. Screening of integracide analogues by SSF and SmF
After 7-days SmF by F. sambucinum, the fermented extract was
obtained by extraction with ethyl acetate thrice from fermentation
broth. The crude extract was subjected to the 1H and 13C NMR mea-
surements, however, the results showed no obvious signals of ster-
oid or integracide analogues (data not shown). In consideration of
that some metabolites not always occurred in SmF (Li et al.,
2015b), a SSF by F. sambucinum was designed and measured. After
30-days SSF, HPLC and TLC analyses were employed to compare
the composition difference between SSF and SmF extracts. The
results revealed that a major component was produced in TLC
and a major peak was observed in HPLC from the extract of F. sam-
bucinum-SSF (Fig. S1). To obtain the preliminary structure informa-
tion, the 1H and 13C NMR and UV–vis spectra measurements were
employed to characterize this crude extract (Fig. S3). Its 1H and 13C
NMR spectra showed that the characterized signals for triterpene
(dH 5.06, 1.89, 1.18–1.24, and 0.74–0.93; dC 131–142, 15–30) and
the signals for saccharides (dH 3.00–3.80; dC 62.9–78.7 and 95.2).
The UV–vis spectrum of F. sambucinum-SSF extract shows one peak
at 221 nm and another typical peak 247 nm which suggesting a
similar structure of the reported triterpene sulfates (Brill et al.,
1996). Subsequently, the major constituent was obtained by using
silica gel CC and Sephadex LH-20 purification to afford compound
1. The 1H and 13C NMR spectra suggested 1 is an integracide ana-
logue. This compound was produced only in SSF, which might
attribute to the longer metabolic circle. It’s reported that more
complex structure secondary metabolites could be obtained gener-
ally from SSF than SmF (Kim et al., 2016; Li et al., 2015b).
1268 J.-W. Dong et al. / Bioresource Technology 218 (2016) 1266–1270

3.2. Identification of sambacide (1) Table 1

The NMR spectroscopic data for 1 in pyridine-d5.a

Compound 1 was isolated as a white amorphous powder, and Position dC dH Position dC dH

its molecular formula was deduced to be C32H50O7S from HRESIMS mult. mult.
at m/z 577.3222 [M-H] (Calcd. for C32H49O7S 577.3204) by using 1 34.6 t a 1.43 (1H, m) 17 49.5 d 2.04 (1H, m)
Agilent MassHunter Workstation Software and was in accord with b 1.02 (1H, m)
1
H and 13C NMR spectroscopic data. The NMR spectra of compound 2 25.0 t a 2.43 (1H, br d, 18 17.1 q 1.22 (3H, s)
J = 10.0 Hz)
1 (Table 1) demonstrated the characteristic NMR features for three b 1.76 (1H, m)
oxy-substituted alkyls [dH 4.27 (1H, m), 4.51 (1H, s), 5.41 (1H, s); dC 3 85.6 d 4.27 (1H, m) 19 22.3 q 1.33 (3H, s)
85.6 d, 68.6 d, 79.2 d], a conjugated double bond [dH 5.46 (1H, s); dC 4 38.9 s 20 33.5 d 1.47 (1H, m)
125.0 s, 140.2 s, 148.0 s, 120.5 d], an anomeric double bond [dH 5 50.6 d 0.96 (1H, m) 21 18.2 q 0.76 (1H, s)
4.59 (2H, d, J = 9.6 Hz); dC 106.5 t, 156.3 s], and an acetyl [dH 1.91 6 18.2 t 1.41 (2H, m) 22 34.7 t a 2.06 (1H, m)
b 1.29 (1H, m)
(3H, s); dC 170.3 s, 21.1 q]. Further comparison of the NMR data 7 27.1 t 2.06 (2H, m) 23 31.1 t a 1.93 (1H, m)
between 1 and integracide A (Brill et al., 1996) and B (Singh b 1.72 (1H, m)
et al., 2003a) revealed that 1 is 2-deoxy integracide A. This is fur- 8 125.0 s 24 156.3 s
ther supported by the 1H–1H COSY correlations from H-2 [dH 9 140.2 s 25 33.8 d 2.00 (1H, m)
10 37.4 s 26 21.9 q 0.77 (3H, s)
2.43 (1H, br d, J = 10.0 Hz); 1.76 (1H, m)] to H-1 [dH 1.43 (1H, m);
11 68.6 d 4.51 (1H, s) 27 21.8 q 0.77 (3H, s)
1.02 (1H, m)] and H-3 [dH 4.27 (1H, m)] and HMBC correlations 12 79.2 d 5.41 (1H, s) 28 106.5 t 4.59 (2H, d,
from H-3 to C-4 (dC 38.9 s), C-29 (dC 16.6 q), and C-30 (dC 28.2 q), J = 9.6 Hz)
from H-2 to C-3 (dC 85.6 d) (Fig. S4A). The HOSO3 located at C-3 13 47.3 s 29 16.6 q 0.75 (3H, s)
14 148.0 s 30 28.2 q 0.93 (3H, s)
was further supported by comparing the 1H NMR chemical shift
15 120.5 d 5.46 (1H, s) 31 170.3 s
of H-3 with literature (Brill et al., 1996; Singh et al., 2003a,b). 16 35.4 t a 2.31 (1H, m) 32 21.1 q 1.91 (3H, s)
Therefore, the planar structure of 1 was identified as 4,4-dimethy b 1.95 (1H, m)
lergosta-8,14,24-triene-3,11,12-triol-12-acetate, 3-sulfate. The a 1 13
H NMR recorded at 400 MHz; C NMR recorded at 100 MHz.
detailed 1H and 13C NMR data of 1 were shown in Table 1 on the
basis of 1H–1H COSY, HSQC, and HMBC correlations.
The relative and absolute configurations of 1 were assigned by
NOESY experiment and comparing the experimental and calcu-
lated electronic circular dichroism (ECD) spectra, respectively.
The H-3 shows 1–3 diaxial cross peaks to H-5 [dH 0.96 (1H, m)]
and CH3-30 [dH 0.93 (3H, s)], and H-5 [dH 0.96 (1H, m)] shows cross
peak to H-1a [dH 1.43 (1H, m)], indicating the 3b-OSO3H, 5a-H con-
figurations. The presence of NOESY correlation from CH3-29 [dH
0.75 (3H, s)] to CH3-19 [dH 1.33 (3H, s)], from CH3-19 to H-11 [dH
4.51 (1H, s)], from H-11 to H-18 [dH 1.22 (3H, s)], and from H-18
to H-20 [dH 1.47 (1H, m)] and CH3-21 [dH 0.76 (1H, s)], suggested
that CH3-19, OH-11, CH3-18, and H-17 are in the b, a, b, and a posi-
tions, respectively. The absence of NOESY correlations from H-12
[dH 5.41 (1H, s)] to CH3-18 and CH3-21 implied the b-OCOCH3 con-
figuration at C-12, because the NOESY correlations from H-12 to
CH3-18 and CH3-21 could be observed in a-OCOCH3 isomers
(Brill et al., 1996; Singh et al., 2003b) (Fig. S4A). As an alternative
approach, the NOESY data were carefully analyzed to assign the
relative configuration of C-20. There were two possible isomers, Fig. 1. Experimental and calculated ECD spectra of 1.
(17aH, 20aH)- and (17aH, 20bH)-forms for 1 and NOESY correla-
tions from H-20 to CH3-18 and H-18b, H-22b to H-16b and H-17
3.3. Antimicrobial activity
supported an assignment of (17aH, 20bH)-configuration (Fig. S4B).
Hence, there are two possible absolute configurations,
The (11b,12a)-isomer of 1 discovered as an antifungal agent has
(3S,5R,10S,11S,12S,13R,17R,20R) and
been reported (Singh et al., 2003a). Hence, three bacteria (Staphy-
(3R,5S,10R,11R,12R,13S,17S,20S) for 1. To clarify the absolute con-
lococcus aureus, Bacillus subtilis, and Escherichia coli) and one fungus
figuration, the ECD data of two possible structures were calculated
(Candida albicans) were selected for estimating the antimicrobial
and compared with experimental spectrum. As shown in Fig. 1, the
activities of 1. Sambacide (1) exhibited strong antibacterial activ-
theoretical ECD data for (3S,5R,10S,11S,12S,13R,17R,20R)-isomer
ity, especially, against S. aureus (MIC: 16 lg/mL, 8 lg/mL for posi-
was in good agreement with the experimental spectrum. Thus
tive control) and E. coli (MIC: 16 lg/mL, 8 lg/mL for positive
the structure of 1 was established as
control) (Table S4), suggesting that sambacide (1) could be used
(3S,5R,10S,11S,12S,13R,17R,20R)-4,4-dimethylergosta-8,14,24-tri
as an antimicrobial agent. However, some integracides without
ene-3,11,12-triol-12-acetate, 3-sulfate and named sambacide,
HOSO3-substituent reported in literature, such as integracides F-J
which is different from the reported (11b,12a)-isomer (Singh
(Ibrahim et al., 2016a,b), showed no obvious antimicrobial activity,
et al., 2003a). Sambacide (1) is a 3-HOSO3-substituted integracide
suggesting that HOSO3- substituent might play an important role
compound. Its analogues are a relatively small class of oxygenated
in antimicrobial activity of these integracide analogues.
tetracyclic 4,4-dimethylergostane triterpenoids, possess a 12-
acetyl-D8,14-diene-11-ol moiety (Ibrahim et al., 2016a).
3.4. Effects of culture media

Potato (Li et al., 2015b), rice bran (Li et al., 2015a; Suresh and
Radha, 2016), rice (Angel-Cuapio et al., 2015), wheat bran (Abu-
 J.-W. Dong et al. / Bioresource Technology 218 (2016) 1266–1270
Tahon and Isaac, 2016), and cornmeal (Tian et al., 2013) frequently
used as the substrates of SSF were used for screening the appropri-
ate fermentation medium. After 30-days SSF, potato-cultured F.
sambucinum processes a significantly high-level production of
sambacide (1) with the yield of 17.27 ± 0.52 g/kg dry weight
(dw), which is significant higher than others (below
1.11 ± 0.26 g/kg) (Fig. S5). As natural carbon and nitrogen sources,
vital minerals, or inducers, the five aforementioned products have
to be the efficient substrates for culturing a majority of fungi. The
significant difference, occurred frequently in different substrates
(Hu et al., 2016), might be ascribed to their different components,
including starch, protein, secondary metabolites, and essential
mineral sources (Li et al., 2015a). Hence, Potato was selected as fer-
mentation substrate for further study.
3.5. Effects of fermentation temperature
Temperature is an important factor effecting on the growth,
enzyme activity, and metabolites of fungi (Muñiz-Márquez et al.,
2016; Pryor et al., 2007; Shams et al., 2011). In the present study,
20 °C, 28 °C, 37 °C, and ambient temperature (range 8–20 °C) were
selected to determine the optimal fermentation temperature for
producing sambacide (1). The growth of strains at 37 °C is obvi-
ously weaker than others. The HPLC determination shows that no
production of sambacide (1) in the extract of SSF-F. sambucinum
at 37 °C. What is noteworthy is that the yield of 28 °C-cultured F.
sambucinum (17.27 ± 0.52 g/kg dw) is significant higher than those
of 20 °C- and ambient temperature-cultured F. sambucinum
(10.19 ± 1.68 g/kg dw and 6.86 ± 0.86 g/kg, respectively) (Fig. S6).
The fermentation temperature of 28 °C was selected as the optimal
temperature which is consistent with the optimum growth tem-
perature of F. sambucinum.
3.6. Effects of fermentation time
Most of fungi can survive for several months in SSF media,
longer than those in SmF survived for several weeks at most. In
the present study, the effects of fermentation time on the growth
of F. sambucinum were evaluated by 5-, 10-, 20-, 30-, and 40-
days SSF. The yields after fermentation reveal that the content of
sambacide (1) significantly increased within 20-days fermentation.
This content stayed the same level of 20-days SSF and decreased
soon afterwards (Fig. S7). This suggests that 20-days fermented F.
sambucinum for producing sambacide (1) is optimal, with the high
yield of 19.04 ± 0.82 g/kg dw. The SSF time of 20 days is less than
those of some traditional Chinese medicines (30–60 days fermen-
tation), such as Bletilla formosana- (Dong et al., 2014), and Aspara-
gus filicinus-fermentation (Li et al., 2015b).
4. Conclusion
A new integracide analogue, sambacide (1), with antibacterial
and antifungal activities, was isolated from SSF with F. sambucinum
B10.2 and identified by HRESIMS, NMR, and ECD spectra. The 20-
days SSF using potato as the fermentation substrate at 28 °C was
obtained and could produce sambacide (1) with a high yield of
19.04 ± 0.82 g/kg dw. This study provides an efficient approach to
produce the antibacterial and antifungal agent sambacide (1) in a
very high yield.
Acknowledgements
This work was financially supported by two grants from the
Natural Science Foundation of China (Nos. 81460536 and
81460648), a grant from New Academic Researcher Award for Doc-
1269
toral Candidates of Yunnan Province (No. 2015-14), and an Under-
graduates Innovative Experiment Project from Yunnan Province
(No. 201510673004).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.biortech.2016.07.
014.
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