Natural Product Research
Formerly Natural Product Letters
Antitubercular metabolites from the marinederived fungus strain Aspergillus fumigatus MF029
Zhijun Song, Yu Liu, Jieyu Gao, Jiansen Hu, Hongtao He, Shengwang Dai,
Luoqiang Wang, Huanqin Dai, Lixin Zhang & Fuhang Song
To cite this article: Zhijun Song, Yu Liu, Jieyu Gao, Jiansen Hu, Hongtao He, Shengwang Dai,
Luoqiang Wang, Huanqin Dai, Lixin Zhang & Fuhang Song (2019): Antitubercular metabolites from
the marine-derived fungus strain Aspergillusfumigatus MF029, Natural Product Research, DOI:
10.1080/14786419.2019.1660331
To link to this article: https://doi.org/10.1080/14786419.2019.1660331
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Published online: 06 Sep 2019.
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Antitubercular metabolites from the marine-derived
fungus strain Aspergillus fumigatus MF029
Zhijun Songa,b, Yu Liuc, Jieyu Gaoa,d
a
CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology,
Chinese Academy of Sciences, Beijing, China; b
University of Chinese Academy of Sciences, Beijing,
China; c
China Astronaut Research and Training Center, Beijing, China; d
School of Food and biological
Engineering, Hefei University of Technology, Hefei, China; e
State Key Laboratory of Bioreactor
Engineering, East China University of Science of Technology, Shanghai, China
ABSTRACT
During the systematic screening of bioactive compounds from
our marine natural product library, crude extract of the marinederived fungus strain Aspergillus fumigatus MF029 exhibited moderate bioactivities against Bacillus subtilis, Staphylococcus aureus,
methicillin-resistant S. aureus, and Mycobacterium bovis bacillus
Calmette–Guerin (BCG). Further chemical investigation resulted in
the identification of two new compounds, chaetominine A (1)
and sphingofungin I (2), together with four known compounds,
emodin (3), chaetominine (4), sphingofungin D (5) and trypacidin
(6). Trypacidin displayed potential antitubercular activity with MIC
CONTACT Lixin Zhang [email protected]; Fuhang Song [email protected] Zhijun Song and Yu Liu contributed equally to this paper.
Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1660331.
2019 Informa UK Limited, trading as Taylor & Francis Group
NATURAL PRODUCT RESEARCH
https://doi.org/10.1080/14786419.2019.1660331
1. Introduction
Tuberculosis (TB) is a major public health threat which leads to thousands of people
death in the world every year (Mandal et al. 2017). Moreover, the evolution of the multidrug-resistant TB (MDR-TB), extensively drug-resistant TB (XDR-TB), and TB/HIV co-infection also causes enormous losses and increases the burden of tuberculosis, especially in
the developing countries. In order to overcome MDR, bedquiline (Mahajan 2013) and
delamanid (Ryan and Lo 2014) were introduced into clinical practice for the treatment
of MDR-TB, but strains with reduced susceptibility to bedaquiline and delamanid were
detected very quickly (Ritter et al. 2015; Zimenkov et al. 2017). Natural product has
been playing an import role in human health (Newman and Cragg 2016), and the new
golden age for natural product drug discovery is coming with the awarded to natural
product research of 2015 Nobel Prize (Shen 2015). During our ongoing efforts to screening novel antibiotics from marine microbial natural product library, a series of active
compounds with antitubercular activity were identified (Chen et al. 2012; Chen et al.
2013; Wang et al. 2013; Song et al. 2014; Zhang et al. 2017).
The genus Aspergillus is an important source for small molecules and has provided
different classes of active secondary metabolites (Zhang et al. 2019), such as alkaloids
(Zhao et al. 2010; Song et al. 2012; Shi et al. 2015), anthraquinones (Zhang, Ma et al.
2012; He et al. 2016), sterigmatocystin analogues (Song et al. 2014), bisabolane-type
sesquiterpenoids (Li et al. 2012), drimane sesquiterpene lactone (Felix et al. 2013),
gliotoxins (Zhao et al. 2009) and isochromanes (Li et al. 2019). In order to investigate
the potential of Aspergillus for active secondary metabolites, a series of A. fumigatus
were isolated from a marine sponge sample of Hymeniacidon perleve collected from
the Bohai Sea, China. The crude extract of an A. fumigatus strain MF029 showed
moderate activity against BCG with an MIC value of 12.5 lg/mL, which was prioritised
for further scaled-up fermentation and chemical studies and resulted in the discovery
of two new compounds, chaetominine A (1) and sphingofungin I (2), together with
four known compounds, emodin (3) (Hawas et al. 2012), chaetominine (4) (Jiao et al.
2006), sphingofungin D (5) (VanMiddlesworth, Wincott et al. 1992; VanMiddlesworth,
Giacobbe et al. 1992) and trypacidin (6) (Gauthier et al. 2012) (Figure 1). Trypacidin
exhibited potential antitubercular activity with MIC value of 1.25 lg/mL.
2. Results and discussion
The strain A. fumigatus MF029 was isolated from a marine sponge sample of H. perleve
collected from the Bohai Sea, China. The ITS gene sequence of MF029 was PCR-amplified, sequenced, and compared to GenBank, which indicated that the strain MF029
was closely associated with the genus Aspergillus and possessed the highest similarity
with Aspergillums fumigatus (100%). Phylogenetic analysis based on ITS gene sequence
revealed that strain MF029 formed a distinct phylogenetic cluster with A. fumigatus
in the phylogenetic tree (Figure S1, Supplementary materials).
Compound 1 was isolated as a white powder, and its molecular formula was deduced
as C22H18N4O5 (HRESIMS m/z 419.1354 [M þ H]þ, calculated for C22H19N4O5, 419.1350),
indicating 16 degrees of unsaturation. The 1
H, 13C and HSQC spectra of 1 (Table S1,
Figure S2–S4, Supplementary materials) revealed 22 carbon signals for three carbonyls
2 Z. SONG ET AL.
at dC 160.0 (C-17), 166.5 (C-15) and 170.3 (C-10), eight aromatic methine signals at dC 124.8
(C-5), 125.4 (C-6), 129.9 (C-7), 114.4 (C-8), 126.4 (C-19), 127.3 (C-20), 134.8 (C-21), 127.2 (C-
22), and four aromatic quaternary signals at dC 136.3 (C-4), 138.8 (C-9), 121.1 (C-18) and
147.3 (C-23) accounting for the two 1,2-disubstitued benzene rings, and one aromatic
methine signal at dC 147.3 (C-25), one sp3 hybrid methylene signal (dC 38.4, C-13), one oxygenated sp3 hybrid methylene at dC (56.6, C-12), three sp3 hybrid methines at dC (82.6, C-
2), (66.1, C-11) and (55.2, C-14), one oxygenated quaternary carbon (dC 76.6, C-3). The 1
H
NMR and 13C NMR data revealed that these data were very similar to those of 4 (Jiao et al.
2006), while the methyl of C-12 in 4 was replaced by an oxygenated methylene (dC 56.6;
dH 4.40 brd (7.2), 3.80, brd (12.0)) in 1. And the oxygenated methylene was confirmed by
the COSY signals (Figure S5, Supplementary materials) from H-11 to H2-12 and the HMBC
cross peaks from H-11 and H-12a to C-10 (Figures S6 and S7, Supplementary materials). All
of these above evidence indicated that the alanine in 4 was replaced by a serine in 1.
From the biosynthetic point of view, the absolute configuration of 1 was deduced as same
as those of chaetominine. Therefore, the structure of 1 was assigned as shown in Figure 1
and named as chaetominine A.
Compound 2 was obtained as a white powder, molecular formula was deduced as
C21H37NO6 (HRESIMS m/z 400.2698 [M þ H]þ, calculated for C21H38NO6, 400.2694). The 1
H and 13C NMR, as well as the HSQC data indicated that compound 2 contained 21
carbons (Table S1, Figures S8–S10, Supplementary materials), including two carbonyl
carbons at dC 173.4 (C-1) and 169.3 (C-21), a pair of trans-double bond carbons at dC
130.2 (C-6) and 131.0 (C-7), four oxygenate methines at dC 70.8 (C-3), 81.8 (C-4), 67.9
(C-5) and 69.5 (C-14), one aminomethine at dC 55.1 (C-2), ten methylene carbons, one
methyl group at dC 22.4 (C-22) for acetyl group, and one methyl group at dC 13.9 (C-
19). By comparing the NMR and MS data with those of sphingofungin D (5)
(VanMiddlesworth, Wincott et al. 1992; VanMiddlesworth, Giacobbe et al. 1992), 2 was
deduced as a cyclized esterification product of 5. And the dihydrofuranone moiety
was confirmed by the HMBC signal from H-4 to C-1. The HMBC cross peak from H-2 to
C-21 revealed the acetyl group of C-21 and C-22. Finally, the structure of 2 was
assigned based on the 1
H-1
H-COSY and HMBC (Figures S7, S11 and S12,
Figure 1. Structures of compounds 1–6.
NATURAL PRODUCT RESEARCH 3
Supplementary materials). The relative configuration of 2 was assigned as same as
those of sphingofungin D (5) based on the biosynthetic pathway. As a result, the
structure of compound 2 was assigned as shown in Figure 1 and named as sphingofungin I.
The bioactivities of these compounds were evaluated against S. aureus, MRSA, B.
subtilis, E. coli and BCG. As show in Table S2 (Supplementary materials), compound 3
displayed moderate antibacterial activities against MRSA and S. aureu with MIC values
of 50 lg/mL, and significant activity against BCG with MIC value of 1.25 lg/mL.
Compound 6 showed moderate antibacterial activities against MRSA and S. aureu with
MIC values of 50 lg/mL, and significant activities against against B. subtilis and BCG
with MIC values of 12.5 and 1.25 lg/mL, respectively.
3. Experimental section
3.1. General experimental procedures
1
H and 13C NMR, along with 2 D-NMR spectra were obtained on a Bruker Avance-600
spectrometer. Chemical shifts were calibrated using residual solvent signals (DMSO-d6:
dH 2.50/dC 39.52). High resolution electrospray ionisation mass spectrometry (HRESIMS)
measurements were obtained on an Agilent Accurate-Mass-Q-TOF LC/MS 6520 instrument. HPLC was performed using an Agilent 1100 Series controlled by ChemStation
Rev.B.02.01. The preparative HPLC system used a reversed phase column (Agilent
ZORBAX, SB-C3, 5 lm, 9.4 250 mm) with a flow rate of 3.0 mL/min.
3.2. Fungal material
The strain A. fumigatus MF029 was isolated from a marine sponge sample of H. perleve
collected from the Bohai Sea, China. It was grown on potato dextrose agar (PDA)
medium slant consisting of potato starch 4.0 g, dextrose 20.0 g and agar 20.0 g in 1.0 L
of distilled water at 25 C. The strain was deposited at the China General
Microbiological Culture Collection Center (accession number No. 3.15764). The nucleotide sequences of ITS gene of A. fumigatus MF029 were deposited in GenBank with
accession number MH974808.
3.3. Fungal culture and identification
A. fumigatus MF029 was identified by phylogenetic analysis using the internal
transcribed spacer (ITS) sequence according to our previous report (Song et al. 2014)
and described as the following: Generally, the primer pair ITS1 (500-TCCG
TAGGTGAACCTGCGG-300) and ITS4 (500-TCCTCCGCTTATT GATATGC-300) were employed
to amplify the ITS region of MF029. PCR amplification (25.0 lL final volume: 0.4 lL
each primer, 2.5 lL 10 buffer, 2.0 lL of 2.5 nM dNTP, 0.4 lL rTaq polymerase and
1.0 lL DNA template) of the ITS sequence was performed on ABI PCR Thermal Cycler
with the initial denaturation at 94 C for 5 min, 25 cycles of denaturation (94 C, 1 min),
annealing (55 C, 1 min), elongation (72 C, 45 s), and a final elongation at 72 C
under aseptic conditions. Then, 6 pieces were used to inoculate three Erlenmeyer
flasks (250 mL), each containing 40 mL of media (Activated potato starch 4.0 g and
dextrose 20.0 g were suspended into 1.0 L of distilled H2O and sterilised by autoclave
at 115 C for 30 minutes). Three flasks with inoculated media were incubated at 28 C
on a rotary shaker at 200 rpm for 5 days to prepare the seed culture. Fermentation
was carried out in 30 Erlenmeyer flasks (1000 mL), each containing 160 g of rice and
distilled H2O (200 mL), then the contents were soaked overnight before autoclaving at
115 C for 30 min. After cooling to room temperature, each flask was inoculated with
5.0 mL of the spore inoculum and incubated at 28 C for 30 days.
The fermented rice substrate was extracted repeatedly with ethyl acetate
(3 500 mL) at room temperature. The organic solvent was evaporated to dryness
under vacuum to afford the crude extract (14.2 g), which was fractionated by vacuum
silica gel column chromatography (8 cm 8 cm) eluted with a gradient of n-hexane:dichloromethane (v/v 100:0, 80:1, 50:1, 32:1, 24:1, 20:1, 15:1, 13:1, 10:1, 9:1, 4:1, 1:1), followed by dichloromethane-methanol (100:0, 5:1, 1:1, 0:100) to give 16 fractions (Frs.
1–16). Fr. 4 (2.012 g) was subjected to Sephadex LH-20 (3.5 cm 50 cm, CH2Cl2/MeOH,
2:1) to give five subfractions (Fr. 4.1–4.5), and Fr. 4.3 (237.8 mg) was further purified by
RP-HPLC (Agilent ZORBAX, SB-C3, 5 lm, 9.4 250 mm) using 70% acetonitrile in water
to afford compound 6 (5.3 mg). Fr. 5 (0.165 g) was subjected to Sephadex LH-20
(2.5 cm 50 cm, CH2Cl2/MeOH, 1:1) to give seven subfractions (Fr. 5.1–5.7), and Fr. 5.3
(57.8 mg) was further purified by RP-HPLC (Agilent ZORBAX, SB-C3, 5 lm, 9.4 250 mm)
using 43% acetonitrile in water to obtain compound 1 (7.0 mg). Fr. 14 (0.257 g) was
subjected to Sephadex LH-20 (2.5 cm 50 cm, CH2Cl2/MeOH 1:1) to give seven subfractions (Fr. 14.1–14.7), and Fr. 14.4 (98.8 mg) was further purified by RP-HPLC
(Agilent ZORBAX, SB-C3, 5 lm, 9.4 250 mm) using 45% acetonitrile in water to afford
compounds 2 and 5 (5.0 mg). Fr.15 (2.235 g) was subjected to Sephadex LH-20 (2.5 cm
50 cm, CH2Cl2/MeOH 1:1) to give seven subfractions (Fr. 15.1–15.7), and Fr. 15.3
(125.8 mg) was further purified by RP-HPLC (Agilent ZORBAX, SB-C3, 5 lm,
9.4 250 mm) using 45% acetonitrile in water to obtain compounds and 3 (4.3 mg)
and 4 (5.0 mg).
White powder, 1
H NMR (600 MHz, DMSO-d6) d: 8.22 (1 H, overlap, H-25), 8.20 (1 H, overlap, H-19), 7.89 (1 H, dd, 7.8, 7.8, H-21), 7.71 (1 H, d, 7.8, H-22), 7.59 (1 H, dd, 7.8, 7.8, H-
20), 7.49 (1 H, d, 7.2, H-8), 7.47 (1 H, d, 7.2, H-5), 7.42 (1 H, dd, 7.2, 7.2, H-7),7.24 (1 H,
dd, 7.2, 7.2, H-6), 6.70 (1 H, s, HO-3), 5.94 (1 H, br s, H-14), 5.63 (1 H, s, H-2), 4.61 (1 H, s,
H-11), 4.40 (1 H, br d, 7.2, H-12a), 3.80 (1 H, br d, 12.0, H-12b), 2.61 (2 H, s, H-13), 13C
NMR (150 MHz, DMSO-d6) d: 170.3 (C-10), 166.5 (C-15), 160.0 (C-17), 147.3 (C-23), 147.3
(C-25), 138.8 (C-9), 136.3 (C-4), 134.8 (C-21), 129.9 (C-7), 127.3 (C-20), 127.2 (C-22),
126.4 (C-19), 124.8 (C-5), 125.4 (C-6), 121.1 (C-18), 114.4 (C-8), 82.8 (C-2), 76.3 (C-3),
66.1 (C-11), 56.6 (C-12), 55.2 (C-14), 38.4 (C-13). Positive HRESIMS: 419.1354 ([M þ H]þ,
C22H19N4O5, calcd 419.1350)
NATURAL PRODUCT RESEARCH 5
White powder, 1
H NMR (600 MHz, DMSO-d6) d: 8.34 (1 H, d, 7.8, H-20), 5.76 (1 H, d, 4.2,
HO-3), 5.65 (1 H, dt, 15.0, 7.2, H-7), 5.51 (1 H, dd, 15.0, 6.0, H-6), 5.14 (1 H, d, 4.2, HO-5),
4.51 (1 H, dd, 8.4, 7.8, H-2), 4.44 (1 H, m, H-3), 4.38 (1 H, brs, H-5), 4.30 (1 H, d, 7.2, H-4),
4.18 (1 H, d, 4.8, HO-14), 3.35 (1 H, m, H-14), 2.00 (2 H, m, H-8), 1.86 (3 H, s, H-22),
1.32(2 H, m, H-9), 1.30 (2 H, m, H-13), 1.29 (2 H, m, H-15), 1.26 (2 H, m, H-18), 1.25 (2 H,
m, H-10), 1.25 (2 H, m, H-11), 1.25 (2 H, m, H-12), 1.24 (2 H, m, H-16), 1.23 (2 H, m,
H-17), 0.86 (3 H, t, 7.2, H-19), 13C NMR (150 MHz, DMSO-d6) d: 173.4 (C-1), 169.3 (C-21),
131.0 (C-7), 130.2 (C-6), 81.8 (C-4), 70.8 (C-3), 69.5 (C-14), 67.8 (C-5), 55.1 (C-2), 37.2
(C-13), 31.6 (C-8), 31.3 (C-17), 29.1 (C-16), 28.9 (C-10), 28.6 (C-9), 28.6 (C-11), 28.6 (C-12),
25.2 (C-15), 22.4 (C-22), 22.0 (C-18), 13.9 (C-19). Positive HRESIMS: 400.2698 ([M þ H]þ,
C21H38NO6, calcd 400.2694)
3.5. Antimicrobial assays
Antibacterial assays were performed according to the Antimicrobial Susceptibility
Testing Standards outlined by the Clinical and Laboratory Standards Institute using
S. aureus (ATCC 6538), MRSA (clinical strain from Chaoyang Hospital, Beijing, China),
B. subtilis (ATCC 6633), E. coli (ATCC 25922), E. faecalis and P. aeruginosa (ATCC 15692)
as testing strains (Huang et al. 2016).
3.6. Anti-Mycobacterium bovis bacillus Calmette-Gu
erin assay
The Anti-BCG assays were carried out by using a strain with constitutive GFP
expression (pUV3583c-GFP) through direct readout of fluorescence as a measure of
bacterial growth (Wang et al. 2013).
4. Conclusion
Chemical studies on the marine-derived fungus strain Aspergillus fumigatus MF029 led
to the identification of two new compounds, chaetominine A (1) and sphingofungin I
(2), together with four known compounds (3-6). In our assay, emodin (3) and
trypacidin (6) displayed significant activity against BCG with MIC values of 1.25 and
1.25 lg/mL, respectively. Emodin (3) was reported to show a series of activities with
anti-cancer, antibacterial and inhibition of Hepatitis C virus (HCV) protease (Hawas
et al. 2012), suppressing silica-induced lung fibrosis (Yang et al. 2016), antidiabetic
potential (Abu Eid et al. 2017), antitubercular (Dey et al. 2014) and anti-inflammatory
(Ngan et al. 2017). Trypacidin (6) was reported to inhibit the growth of parasites
(Balan et al. 1963), be cytotoxic (Gauthier et al. 2012), anti-bacteria and fungi
(Zhang, Ma et al. 2012; Zhang, Li et al. 2012, Pinheiro et al. 2013). This is the first
report that trypacidin displayed potential antitubercular activity, which will promote
the investigation on antitubercular secondary metabolites from fungi.
Disclosure statement
The authors declare that they have no conflicts of interest.
6 Z. SONG ET AL.
Funding
This work was supported by grants from the National Key R&D Program of China
(2018YFC0311001, 2017YFD0201203, 2017YFC1601300), the Key Lab of Marine Bioactive
Substance and Modern Analytical Technique, SOA, and the National Natural Science Foundation
of China (31600136, 31720103901), and Taishan Scholarship for Lixin Zhang.
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