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Characterisation of the metabolites


of an antibacterial endophyte
Botryodiplodia theobromae Pat. of
Dracaena draco L. by LCMS/MS
ab

Ahmed M. Zaher , Ahmad M. Moharram , Richard Davis , Peter


a

Panizzi , Makboul A. Makboul & Angela I. Caldern

Department of Drug Discovery and Development, Harrison School


of Pharmacy, Auburn University, 4306 Walker Building, Auburn,
AL36849, USA

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Department of Pharmacognosy, Faculty of Pharmacy, Assiut


University, Assiut, Egypt
c

Mycology Center, Faculty of Science, Assiut University, Assiut,


Egypt
Published online: 19 Feb 2015.

To cite this article: Ahmed M. Zaher, Ahmad M. Moharram, Richard Davis, Peter Panizzi, Makboul
A. Makboul & Angela I. Caldern (2015): Characterisation of the metabolites of an antibacterial
endophyte Botryodiplodia theobromae Pat. of Dracaena draco L. by LCMS/MS, Natural Product
Research: Formerly Natural Product Letters, DOI: 10.1080/14786419.2015.1012715
To link to this article: http://dx.doi.org/10.1080/14786419.2015.1012715

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Natural Product Research, 2015


http://dx.doi.org/10.1080/14786419.2015.1012715

Characterisation of the metabolites of an antibacterial endophyte


Botryodiplodia theobromae Pat. of Dracaena draco L. by LC MS/MS
Ahmed M. Zaherab, Ahmad M. Moharramc, Richard Davisa, Peter Panizzia,
Makboul A. Makboulb and Angela I. Calderona*
a

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Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, 4306
Walker Building, Auburn, AL 36849, USA; bDepartment of Pharmacognosy, Faculty of Pharmacy, Assiut
University, Assiut, Egypt; cMycology Center, Faculty of Science, Assiut University, Assiut, Egypt
(Received 26 September 2014; final version received 21 January 2015)

Botryodiplodia theobromae Pat. belongs to the endophytic fungi that live within the
tissues of medicinal plants and produce bioactive natural products. The endophyte was
isolated from the leaves of Dracaena draco L. The LC MS-based metabolite
fingerprinting of the ethyl acetate extract of B. theobromae with antibacterial activity
led to the identification of 13 metabolites pertaining to various classes: dipeptides
(maculosin and L,L-cyclo(leucylprolyl), alkaloid (norharman), coumarin and
isocoumarins (bergapten, meranzin and monocerin), sesquiterpene (dihydrocumambrin
A), aldehyde (formyl indanone), fatty alcohol (halaminol A) and fatty acid amide
(palmitoleamide, palmitamide, capsi-amide and oleamide). This study reports for the
first time, the LC MS and LC MS/MS identification of 13 known bioactive metabolites
from the antibacterial ethyl acetate extract of B. theobromae isolated from the leaves of
D. draco L.
Keywords: Botryodiplodia theobromae; LC-MS/MS; metabolite fingerprinting;
antibacterial

1. Introduction
Endophytic fungi live within the aerial tissues of their host plants and protect them from
attacking by insects, pests, pathogens and domestic herbivores (Malinowski & Belesky 2006).
Endophytes produce therapeutic bioactive compounds similar to those of their host plants
(Strobel & Daisy 2003) and are considered as an alternative source of bioactive natural products
(Strobel 2002; Strobel & Daisy 2003; Kumar & Hyde 2004; Huang et al. 2008). More
specifically, the endophytes are a rich source of antimicrobial compounds such as alkaloids

*Corresponding author. Email: aic0001@auburn.edu


q 2015 Taylor & Francis

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A.M. Zaher et al.

(Powell & Petroski 1993), steroids (Ding et al. 2010), terpenoids (Schulz et al. 2002) and
flavonoids (Yu et al. 2010).
Palmarumycins are antibacterial and antifungal metabolites (Kanoh et al. 2008) that have been
isolated from endophytes including Lasiodiplodia (Lu et al. 2014). Palmarumycin LP1,
cladospirone B and ascochytatin are examples of cytotoxic palmarumycins isolated from
Lasiodiplodia (Botryodiplodia) pseudotheobromae (Lu et al. 2014). The endophyte
Botryodiplodia theobromae Pat., which is a common fungus in tropical and subtropical regions
all over the world, has previously been isolated from different medicinal plants (Miersch et al.
1991; Pandi et al. 2010; George et al. 2011). Several natural products such as anticancer taxol
(Pandi et al. 2010), chitosan (George et al. 2011), phytohormones (Miersch et al. 1991; Castillo
et al. 2014) and cyclohexenone compounds (plant growth factors) (Takel et al. 2008; Kitaoka et al.
2009) have been reported in the endophyte.
Liquid chromatography coupled to mass spectrometry (LC MS) is widely used as a
powerful modern tool for qualitative and quantitative analysis of the complex plant and fungal
extracts (Wu et al. 2012). Because of the diversity in chemical structures and the lack of
authentic standards of most of the fungal metabolites, the use of LC MS analytical technique is
considered to be the best hyphenated technique for a rapid separation and accurate identification
of the compounds in complex mixtures.
In our study, B. theobromae was isolated from the medicinal plant Dracaena draco L. and
the ethyl acetate extract of the endophyte was analysed by using LC MS and LC MS/MS for
chemical profiling of the B. theobromae extract. In addition, the antibacterial inhibitory activity
of the ethyl acetate extract was determined based on the bacterial growth inhibition at 0.06 and
0.15 mg.
2. Results and discussion
2.1. LC MS and LC MS/MS analysis of the B. theobromae extract
The extract ion chromatogram of B. theobromae extract is shown in Figure S3, where the peaks
of 13 identified compounds were numbered according to their retention times. The identification
of metabolites in the ethyl acetate extract was achieved by LC MS and LC MS/MS analysis by
using QTOF mass spectrometer in both positive and negative electrospray ionisation (ESI)
modes. In addition to the 13 identified compounds (Figure 1), two more peaks at the retention
times of 15 and 39.94 min were detected in the ( ) ESI mode (Figure S3). The structures of the
compounds corresponding to the two additional peaks could not be established based only on the
MS data obtained in this study. However, the total ion chromatogram of the extract did not show
the presence of any ionisable compound in the negative ESI mode.
The identification of fungal metabolites was based on accurate mass measurement, molecular
formula, double bond equivalent (DBE), MS/MS fragmentation (Table S1) and comparison with
previously available MS data. The identified compounds by using LC MS were not isolated or
purified from the total extract.
Compound 1 (tR10.40 min) displayed a protonated molecule at m/z 261.1237 [M H]
with molecular formula C14H16N2O3, DBE 8 supporting two cyclic rings, two carbonyl
groups and a benzene ring. MS/MS fragmentation showed peaks at m/z 136.0753 [M H125.0484] representing the loss of C6H7NO2, m/z 107.0491 [M H-C6H7NO2-CH2NH] and
m/z 91.0544 for a [C7H7] which was in accordance with the MS fragmentation pattern of
maculosin reported by Nielsen and Smedsgaard (2003). Maculosin was isolated previously from
fungus Penicillium canescens Sopp (Vansteelandt et al. 2012) and this is its first report in the
genus Botryodiplodia.
Compound 2 (tR10.95 min) showed a protonated molecule [M H] at m/z 169.0760
with molecular formula C11H8N2, DBE 9 supporting two benzene rings and one cyclic ring.

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Natural Product Research

Figure 1. Compounds identified in the ethyl acetate of B. theobromae by ( )-ESI LC MS.

MS/MS fragmentation showed peaks at m/z 142.0645 [M H-27.0115] with loss of HCN and
m/z 115.0540 [M H-54.022] with loss of two molecules of HCN which corresponded to the
MS fragmentation pattern of norharman (Crotti et al. 2010). Compound 2 (norharman) was
previously reported in the endophyte Epichole amarillans Pert (Kuldau & Bacon 2008) and
found for the first time in the species under study. Compound 3 (tR 11.37 min) presented a
protonated molecule at m/z 211.1437 [M H] with molecular formula C11 H18N2O2, DBE 4
supporting two carbonyl groups and two cyclic rings. MS/MS fragmentation showed peaks at

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A.M. Zaher et al.

m/z 114.0914 [M H-97.0523] with loss of C5H7NO group, m/z 86.0968 [M H-C5H7NOCO], m/z 70.0658 [M H-C7H11NO2] which matched the fragmentation pattern of L ,L -cyclo
(leucylprolyl) and was isolated previously from the fungus Alternaria alternata Kiesl (Stierle
et al. 1988), and first reported here. Compound 4 (tR 11.52 min) displayed a protonated
molecule at [M H]m/z 217.0487 with molecular formula C12H8O4, DBE 9 supporting a
benzene ring, two double bonds, and two cyclic rings. MS/MS fragmentation showed peaks at m/
z 189.0537 [M H-27.995] with loss of CO group which was similar to that of bergapten
(Dincel et al. 2013). This compound had been previously reported in celery infected with
Sclerotinia sclerotiorum Hence (Wu et al. 1972). This is the first report on the presence of
bergapten in the genus Botryodiplodia. Compound 5 (tR 11.78 min) showed a protonated
molecule at m/z 261.1118 [M H] with a molecular formula C15H16O4, DBE 8 supporting a
benzene ring, two cyclic rings and two double bonds. MS/MS fragmentation showed peaks at m/
z 243.1007 [M H-18.0111] with loss of H2O and m/z 189.1102 [M H-C4H7O]. The MS
fragmentation was typical for the fragmentation pattern of meranzin (Dugo et al. 2000).
Meranzin was isolated previously from citrus essential oils (Dugo et al. 2000). This is the first
report of meranzin in this species. Compound 6 (tR 13.09 min) presented a protonated
molecule at m/z 309.1691 [M H] with molecular formula C17H24O5, DBE 6 supporting 3
double bonds and 3 cyclic rings. MS/MS fragmentation showed peaks at m/z 291.1608 [M HH2O] and m/z 81.0722 [M H-C11H16O5]. The fragmentation pattern was similar to that of
dihydrocumambrin A which was isolated previously from Chrysanthemum coronarium L. (ElMasry et al. 1984) and identified for the first time in this endophytic fungus. Compound 7
(tR 14.77 min) displayed a protonated molecule at m/z 161.0594 [M H] with formula
C10H8O2, DBE 7 supporting benzene ring, two carbonyl groups and one cyclic ring and MS/
MS fragmentation showed fragments at m/z 133.0641 [M H-27.9953] corresponding to the
loss of carbonyl group, m/z 105.0715 [M H-2CO] with loss of two carbonyl groups. This is
in concordance with the fragmentation pattern of formyl indanone which was isolated previously
from the fungus Arthrobacter sp. strain F101 (Casellas et al. 1997) and reported for the first time
here. Compound 8 (tR 16.56 min) showed a protonated molecule at m/z 309.1333 [M H]
with molecular formula C16H20O6, DBE 7 supporting one double bond, a benzene ring and
two cyclic rings. MS/MS fragmentation showed peaks at m/z 291.1215 [M H-H2O], m/z
249.0745 [M H-C3H8O], m/z 193.0481[M H-C6H12O2]. The fragmentation pattern was
similar to that of monocerin (Zhang et al. 2008). Based on MS data, compound 8 was identified
as monocerin which was isolated from the endophytic fungus Microdochium bolleyi Sprague
(Zhang et al. 2008) and from the fungus Fusarium larvarum Fuckel (Claydon et al. 1979). But
this study reports monocerin for the first time in the endophytic fungus under study. Compound 9
(tR 34.10 min) presented a protonated molecule [M H] at m/z 228.2321 with molecular
formula C14H29NO, DBE 1 indicating one double bond. MS/MS fragmentation showed peaks
at m/z 102.0910 [M H-C9H18], m/z 88.0756 [M H-C10H20], m/z 43.0550 [M HC11H23NO]. Compound 9 corresponded to halaminol A based on MS data (Balderas et al.
2013). Halaminol A was isolated previously from the tropical marine sponge of Haliclona
sp. (Clark et al. 2001) but has been detected for the first time in endophytic fungi. Compound 10
(tR35.27 min) displayed a protonated molecule at m/z 254.2478 [M H] with molecular
formula C16H31NO, DBE 2 indicating two double bonds. MS/MS fragmentation showed a
peak at m/z 69.0705 [M H-185.1773] loss of C11H23NO. Compound 10 was confirmed as
palmitoleamide based on MS and MS/MS data (Nichols et al. 2007) and belongs to fatty acid
amides which are naturally present in plants and fungi (Kim et al. 2010). Compound 11
(tR 37.07 min) showed a protonated molecule at m/z 256.2641 [M H] with molecular
formula C16H33NO, DBE 1 indicating the presence of one double bond. MS/MS
fragmentation showed peaks at m/z 102.0917 [M H-154.1724] due to the loss of C11H22,
m/z 88.0765 [M H-C11H22-CH2] and m/z 43.0554 for [C3H7]. This MS fragmentation

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Natural Product Research

pattern agreed with that of fatty acid amide previously reported data (Nichols et al. 2007) and
based on MS and MS/MS data it was identified as palmitamide which are naturally present in
plants and fungi (Kim et al. 2010). Compound 12 (tR 38.68 min) presented a protonated
molecule at m/z 270.2799 [M H] with molecular formula C17H35NO, DBE 1 indicating
the presence of one double bond. MS/MS fragmentation showed peaks at m/z 116.1072
[M H-154.1727] with the loss of C11H22, m/z 102.0918 [M H-C11H22-CH2] and m/z
43.0555 [M H-C13H29NO]. The fragmentation pattern of compound 12 agreed with that of
fatty acid amide previously mentioned in compound 11. Compound 12 is a capsi-amide
according to MS data (Table S1). This fatty acid amide has been previously isolated from
Capsicum annuum L. (Takahashi et al. 1980) and reported for the first time in endophytic fungi.
Compound 13 (tR 39.94 min) displayed a protonated molecule at m/z 282.2799 [M H]
with molecular formula of C18H35NO, DBE 1 indicating one double bond. MS/MS
fragmentation showed peaks at m/z 97.1016 [M H-85.1783] with the loss of C11H25, m/z
83.0855 [M H-C11H25-CH2] and m/z 55.0552 [M H-C14H29NO]. The fragmentation
pattern of compound 13 agreed with that of fatty acid amide previously mentioned above in
compound 11. Based on the MS data, it was identified as oleamide which is naturally present in
plants and fungi (Kim et al. 2010).
The production of the secondary metabolites from the endophytic fungi is influenced by
general environmental factors such as culture media composition (carbon and nitrogen sources),
temperature, light, pH and their host plant interactions on the production of the secondary
metabolites of the endophytic fungi (Aly et al. 2010). Examples of the effect of the environmental
factors (culture media composition and host plants interactions) on the production of the
secondary metabolites of the endophyte under study are described as follows: (1) detection of
some phytohormones such as jasmonic acid, indole-3-propionic acid, indole-3-butyric acid and
gibberellic acid from the fermented broth of the B. theobromae isolated from Citrus sinensis
Osbeck (Castillo et al. 2014); (2) identification of chitosan from the fungus B. theobromae
isolated from leaves and bark of some medicinal plants (George et al. 2011) and (3) isolation of
anticancer taxol from B. theobromae isolated from Morinda citrifolia Linn (Pandi et al. 2010).
But in our study, the fungus B. theobromae was isolated from the leaves of D. draco L and
cultivated in MID medium. For the first time, 13 compounds of different classes were detected in
the extract of the endophyte by using LC MS.
2.2. Antibacterial activity of B. theobromae ethyl acetate extract
The ethyl acetate extract of B. theobromae at the amount of 0.06 and 0.15 mg showed
characteristic inhibition zones (mm) against tested Gram-positive and Gram-negative bacteria
based on the comparison to the inhibition zone of ampicillin discs as a positive control (Table S2).
Also, some of the detected compounds (meranzin and monocerin) in the extract of B. theobromae
were previously isolated from other natural sources and tested for their antibacterial activity
against Staphylococcus aureus and Escherichia coli (Mokbel & Suganuma 2006; Zhang et al.
2008). Compound 8 (monocerin) is an antibacterial fungal metabolite, and its mechanism of
action was previously proven by interference with selected stages of the cell division cycle of the
pathogenic bacteria S. aureus and E. coli (Mokbel & Suganuma, 2006).
3. Conclusions
The LC MS-based metabolite characterisation and profiling method enabled the identification
of 13 known (but reported for the first time in the genus) compounds from the ethyl extract
of B. theobromae on the basis of accurate mass measurement, molecular formula, DBE and MS/
MS fragmentation in ( ) ESI and a comparison with the relevant data from the literature.

A.M. Zaher et al.

In addition, the ethyl acetate extract of B. theobromae showed high antibacterial activity
(11 # d # 20 mm) against the tested Gram-negative bacteria E. coli Xen14 and E. coli 10G, and
the Gram-positive bacteria S. aureus Xen31 (MRSA) and S. aureus Xen 29 (MSSA).
Supplementary material
Experimental details relating to this paper are available online, alongside Tables S1 and S2 and
Figures S1 S6.
Acknowledgements

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Authors are indebted to the Joint Supervision Program of Egypt (2013-2015) for financial support to
A. M. Zaher.

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