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Endophytic fungi--the treasure chest of antibacterial substances.



Endophytic fungi



Bacterial resistance


Over more than 20 years, the endophytic fungi have been explored as "biofactories" of novel bioactive substances, and they have not disappointed. Among the extracts and pure substances obtained from the culture broths or fungal biomass, some have exerted antibacterial activity ranging from moderate to powerful when tested on the bacterial strains resistant to the antibiotics currently in use. In this article we review the accumulated data on endophytic fungi isolated from plants that produce metabolites with antibacterial activity against human pathogenic bacteria.

[c] 2012 Elsevier GmbH. All rights reserved.


Introduction                     1270

Antibacterial substances         1271
isolated from endophytic

Endophytic fungi producing      1281
metabolites effective
against Helicobacter pylori

Endophytic fungi producers     1282
of the same metabolites
as the host plant

Discussion                    1282

Conflict of interest         1283

Acknowledgments              1283

References                   1283


According to the World Health Organization (WHO) Global Burden of Disease report in the year 2004, cardiovascular diseases were the leading cause of death in the world, particularly among women. Infectious and parasitic diseases were the next leading cause, causing 15.6% of all deaths in women and 16.7% in men, while cancers occupy the third place on the list (WHO, World Health Organization 2008). The World Health Day 2011 campaign, launched by the WHO is offering a strategy to safeguard the existing antibiotics for future generations and contain the spread of antimicrobial resistance. In the battle against the ever-increasing multidrug resistance of human pathogenic bacteria, we urgently need new alternatives to the currently available broad-spectrum antibiotics. Bacterial species recently named as the "ESKAPE" pathogens: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacter species cause the majority of hospital infections and effectively "escape" the effects of antibacterial drugs (Rice 2008). Resistance has increased in both Gram-positive and Gram-negative pathogens, and poses a serious threat to the successful treatment of infectious diseases. Another alarming fact is that the number of new antibacterial drugs that make it through the complete development process and ultimately receive approval has decreased over the past 25 years. Boucher et at. report a 75% decrease in systemic antibacterials approved by the FDA from 1983 through 2007, with evidence of continued decrease in approvals between the years 2003 and 2007 (Boucher et at. 2009). Modern medicine was built on a reliance on antibiotics, but we are now heading towards a world without them, which is why there are more and more initiatives to raise awareness of this problem. European Federation of Pharmaceutical Industries and Associations, the voice of the research-based pharmaceutical industry in Europe, welcomed and supported the launch by the Innovative Medicines Initiative (IMI) a[euro]223,7 million program to tackle antimicrobial resistance and to speed up the development of new antibiotics (EFP1A, European Federation of Pharmaceutical Industries and Associations 2011).

So, where do we look for new antibiotics? Whenever a new niche of biodiversity is discovered and accessed, new natural products are found. The realization that there is a large, and mostly unexplored, group of fungi living inside higher plants (endophytic fungi) led to focused discovery efforts in both industrial and academic laboratories. Plant endophytic fungi are fungal microorganisms which spend all or part of their lifecycle inter- and/or intracellularly colonizing healthy tissues of their host plants, typically causing no apparent disease symptoms (Tan and Zou 2001). Plant endophytic fungi, have the special ability to produce the same or similar compounds originated from their host plants, as well as a great number of diverse bioactive compounds, which have been implicated in the protection of its host against pathogens and herbivores (Wicklow et al. 2005). These structurally diverse molecules have potential therapeutic value which is why people's interest in screening endophytic fungi for discovery of novel metabolites, and more specifically novel antibiotics, has increased. The natural product that is mostly "to blame" for the recognition of plant enclophytic fungi as an important source of natural bioactive products is paclitaxel (taxol) due to the discovery of the taxol producing endophytic fungus Taxomyces andreanae in 1993 (Stierle et al. 1993).

Endophytic fungi have been found in each plant species examined, and it is estimated that there are over one million endophytic fungi existing in nature (Petrini 1991). Since the first endophytic fungus was identified, a lot of attention has been given to the potential of exploitation of these fungi for the production of novel antibiotics. This niche should be meticulously investigated and used as a base for sustainable research and development of new antibacterial substances that can both respond to current antimicrobial resistance and anticipate evolving resistance. This paper reviews the data concerning the research of new antibacterial substances against human pathogenic bacteria produced by endophytic fungi isolated from plants.

The discovery of new species of endophytic fungi continues as well as the discovery of novel antibacterial substances. The reasoning behind host plant selection has mostly been to investigate plants that are used in traditional medicine for the treatment of infections and identify the enclophytic fungi found in different parts of those plants. The success of discovering naturally occurring therapeutic agents depends on bioassay-guided fractionation and purification procedures. Fractionation of the culture broth and mycelium extract leads to the isolation of the metabolite responsible for the antibacterial activity. In the following text we review the results of antibacterial testing of crude extracts and purified substances obtained from different enclophytic fungi. We try to list them in alphabetical order of the genus of the tested fungi as far as possible. Presented in Table 1 are endophytic fungal strains, host plant from which they were isolated, the host plant's habitat, type of extract or secondary metabolite with antibacterial activity, strains of human pathogenic bacteria and the method used for antibacterial testing and the literature references.

Endophytic fungal     Host plant(s) (family),      Habitat of
strain                plant                        the
                      part or tissue               host plant

Phomopsis isolate     Salix gracilistyla var.      Acquisition
MF6031                Melanostachys (Salicaceae);  number
                      twig                         237-71-5282.
                                                   Place. UK

Unidentified          Daphnopsis americana         Guanacaste
endophytic fungus     (Thymelaeaceae); branch      Conservation
CR115                                              Area in Costa
Colletotrichum sp.    Artemisia annua L.           ns
                      (Asteraceae); stem

Guignardia sp.        Spondias mombin L            Para and Rio
                      (Anacardiaceae); leaf and    de
                      twig                         Janeiro

Colletotrichum        Artemisia mongolica (Fisch.  Zijin
gloeosporioides                                    Mountain,
                      ex Bess.) Nakai              the suburb of
(Penz.)Penz.&Sacc.    (Asteraceae);                Nanjing.
13 isolates of        stem                         China

                      Aspidosperma tomentosum      Rio de

                                                   city (Morrodo
Phomopsis sp.         (Apocynaceae); leaf          Entorno,
                      Spondias                     do
                                                   and the
                      mombin L (Anacardiaceae);    Brazilian
                                                   Amazon forest
                      twig                         near Redencao
                                                   (Para state)

Periconia sp.OBW-15   Taxus cuspidate Siebold &    Kangwon

                      Zucc (Taxaceae); small       region,
                      branch                       Korea

Rhizoctonia sp.       Cynodon dactylon (L)         Jiangsu
strain Cy064          Pers.(Poaceae): leaf         Province

Fusarium sp. IFB-121  Quercus variabilis           Southern
                      Blume(Fagaceae);bark         hillside of
                                                   in the
                                                   suburb of

Phornopsis sp.        Erythrina crista-galli L     Boraso
strain                (Fabaceae): twig             Stream-Delta
E02018                                             del Parana.

Aspergillus sp.       Cynodon dactylon (L.) Pers.  Sheyang Port
strain CY725          (Poaceae); leaf              on
                                                   the Yellow

Ampe/omyces sp.       Urospermum picroides (L)     Alexandria.
                      F.W.Schmidt (Asteraceae);    Egypt

Phoma sp. NG-25       Saurauia scaberrinae         Central
                      (Actinidiaceae); stem        highlands of
                                                   Papua New

Thielavia             Hypericum perforatum L       Harwan. Jammu
subthermophila        (Hypericaceae); stem         and Kashmir.
INFU/Hp/KF/34B                                     India

Xylaria sp. YX-28     Ginko biloba L               Jiangsu and
                      (Ginkgoaceae);               Shandong
                      twig                         Provinces.

Pichia                Paris polyphylla var.        Kunming.
guilliermondii        yunnanensis (Franch)
Ppf9                  Hand.-Mazz. (Trilliaceae);

15 endophytic fungi   Dracaena cambodiana          Jinghong
with antibacterial    (Asparagaceae); leaf, root   city,
activity              and stem Aquilaria sinensis  Xishuangbanna
                      (Lour.)Spreng.               prefecture.
                      (Thymelaeaceae); leaf,       Yunnan. China
                      and stem

24 endophytic fungi   43 plant samples; leaf,      Two locations
(with moderate        stem,                        in the
antibacterial         root, rhizome, flower,       National
activity)             fruit                        Park, Pahang,
                      and bark                     Malaysia

Unidentified          Melilotus dentatus (Waldst   Coastal area
                      &                            of
                      SiKit.) Pers. (Fabaceae);
                      ns                           the Baltic

Ascomycete                                         Sea,
endophytic                                         Ahrenshoop,
fungus strain 6650                                 Germany

Chlohdium sp.         Azadirachta indica A. Juss.  Varanasi
(J.F.H.               (Meliaceae); root            district,
Beyma)W. Gams &                                    India

Altemaria sp. strain  Sonneratia alba J.E. Smith   DongZhai Gang
JCM9.2                (Sonneratiaceae); leaf       Mangrove
                                                   on Hainan
                                                   Island. China

Micwdiplodia sp.      Erica arborea L              Gomera. Spain

strain 7092           (Ericaceae);                 Playa del
                      ns                           Ingles.
Microsphaeropsis sp.  Lyrium mtricarum Boiss.      Spain
strain 8875           (Solanaceae); ns

Microsphaeropsis sp.  Zygophylium                  Gomera, Spain
strain 7177           fortanesii(Zygophyllaceae);

Twenty-nine           Eucommia ulmoides Oliver     Sichuan
unidentified          (Eucommiaceae); stem         University.
endophytic fungal                                  Chengdu,
strains                                            Sichuan

F. solani 2,          Dendrobium loddigesii        Nature

Bionectria sp 2. 15   Rolfe(Orchidaceae;); root.   of Pogang,
other strains         stem, and leaf               Xingyi,

Trichoderma           Panax notoginseng (Burkill)  Yunnan
ovalisporum PRE-5     F.H.Chen ex C.Y. Wu & K.M.   Province.
                      Feng (Araliaceae); root      China

Xylaria sp. NCY2      Torreya jackii Chun          Jiangshi
                      (Taxaceae)                   Reserve Zone

Endophytic fungal     Crude extract/isolated
strain                metabolite

Phomopsis isolate     * Phomopsichalasin
MF6031                * Guanacastepenes A-0
endophytic fungus

Colletotrichum sp.    * 6-lsoprenylindole-
                      3-carboxylic acid
                      * 3b,5a-Dihydroxy
                      * 3b-Hydroxy -
                      * 3-Oxo-ergosta -
                      4.6,8(14), 22-tetraene
                      * 3b-Hydroxy-5a,

Guignardia sp.        * Ethyl acetate crude
Colletotrichum        extract of culture broth
gloeosporioides       * Colletotric acid
13 isolates of

                      * Ethyl acetate crude
                      extracts of cultivation

Phomopsis sp.

Periconia sp.OBW-15   * Periconicin A
                      * Periconicin B

Rhizoctonia sp.       * Rhizoctonic acid
strain Cy064          * Monomethylsulochrin
                      * Ergosterol
                      *3[BETA], 5[alpha],

Fusarium sp. IFB-121  * Cerebroside 1
                      * Cerebroside 2

Phornopsis sp.        * Phomol

Aspergillus sp.       * Helvolicacid
strain CY725          * Monomethylsulochrin
                      * Ergostero
                      * 3f3-Hydroxy -5a,
                      8a-epidioxy- ergosta-6,

Ampe/omyces sp.       * 3-O-methylalaternin
                      * Altersolanol A

Phoma sp. NG-25       * Phomodione
                      * Usnicacid
                      * Cercosporamide

Thielavia             * Hypericin
subthermophila        * F.modin

Xylaria sp. YX-28     * 7-Amino-4

Pichia                * Helvolicacid

15 endophytic fungi   * Crude extract
with antibacterial    * Crude ethyl acetate
activity              extract from mycelium and
24 endophytic fungi   culture
(with moderate        agar combined

Unidentified          * 4-Hydroxyphthalide;
                      -7- hydroxyphthalide

Ascomycete            * (3R.4R)-cis
endophytic            -4-hydroxymellein
fungus strain 6650

Chlohdium sp.         * Javanicin
Beyma)W. Gams &

Altemaria sp. strain  * Xanalteric acid I
JCM9.2                * Xanaltericacid II
                      * Altenusin

Micwdiplodia sp.      *
strain 7092           3.4-Dihydroglobosuxanthone
                      * Microsphaeropsone A
                      * Microsphaeropsone C

Microsphaeropsis sp.  * Citreorosein
strain 8875           * Enone (oxidized
                      microsphaeropsone A)
Microsphaeropsis sp.  * Fusidienol A
strain 7177           * 8-Hydroxy- 6-methyl-
                      xanthene-1- carboxylic
                      acid methyl ester

Twenty-nine           * Crude ethanol extract of
                      fermentation broth
unidentified          * Chlorogenic acid
endophytic fungal

F. solani 2,          * Ethyl acetate extract of
                      the culture filtrate
Bionectria sp 2. 15
other strains

Trichoderma           * Koninginin A
ovalisporum PRE-5     * (E)-2.3- dihydroxypropyl
                      octadec- 9-enoate
                      * Shikimicacid
                      * Cytosine ribonudeoside A
                      compound considered to be
                      adenine ribonudeoside

Xylaria sp. NCY2      * 1-(XylarenoneA)
                      xylariate A.
                      * Xylarioicacid B,
                      * Xylariolide A,
                      * Xylariolide B,
                      * Xylariolide C,
                      * Methyl xylariate C,
                      * Xylariolide D
                      * Taiwapyrone

Endophytic fungal     Test bacteria

Phomopsis isolate     * B. subtilis
MF6031                * Enterococcus
                      * P. aeruginosa
                      * S. aureus

Unidentified          *
endophytic fungus     Methicillin-resistant
CR115                 S. aureus
                      E. faecalis

Colletotrichum sp.    * B.subiilis
                      * S. saureus
                      * Sarcina lutea
                      * Pseudornonas sp.

Guignardia sp.        * S. aureus
                      * E. coli

Colletotrichum        * B. subtilis
gloeosporioides       (Ehrenberg) Cohn
(Penz.)Penz.&Sacc.    * S. aureus Rosenbach
13 isolates of        * Sarcina lutea
                      * Pseudornonas sp.
                      * E.coli(ATCC 25922)
                      * P. aeruginosa (ATCC

Phomopsis sp.         27853)
                      * S. aureus (ATCC

Periconia sp.OBW-15   * E. coli (ATCC
                      * K. pneumoniae (IFO
                      * P. vulgaris (ATCC
                      * S. typhimurium
                      * B.subtilis (ATCC
                      * M.leu teus (IFO
                      * S. aureus (ATCC
                      * S. epidermis (ATCC

Rhizoctonia sp.       * H. pylori (ATCC
strain Cy064          43504) * Five
                      selected clinical
                      strains from antral
                      biopsies from
                      and adults
Fusarium sp. IFB-121  * B. subtilis
                      * E. coli

Phornopsis sp.        * Artbrobacter
strain                citreus
E02018                * Corynebacterium
                      * Pseudomonas
                      * E. coli
                      * B. subtilis

Aspergillus sp.       * H. pylori (ATCC
strain CY725          43504)
                      * Five clinical
                      isolates obtained
                      antral biopsies of
                      child and adult
                      * B. subtilis,
                      * P. fluoresceins,
                      * E. coli,
                      * 5. lutea
                      * S. aureus

Ampe/omyces sp.       * S. epidermidis

                      * S. aureus
                      * E. faecaiis
Phoma sp. NG-25       * S. aureus (ATCC
                      * E.coli (Life
                      Technology 18290-015)

Thielavia             * S. aureus ssp.
subthermophila        aureus (DSM 799)
INFU/Hp/KF/34B        * K. pneumoniae ssp.
                      ozaenae (DSM681)
                      * P. aeruginosa (DSM
                      * Salmonella enterica
                      ssp. enterica (DSM
                      * E.coli (DSM 682)

Xylaria sp. YX-28     * S. aureus
                      * E. coli
                      * S. typhi
                      * S. typhimurium
                      * S. enteritidis
                      * Aeromonas
                      * Yersinia sp.
                      * V. anguillawm
                      * Shigella sp.
                      * V. parahaemolyticus

Pichia                * E.coli (ATCC
guilliermondii        29425),
Ppf9                  * B. subtilis (ATCC
                      * S. aureus (ATCC
                      * S. haemolyticus
                      (ATCC 29970)

15 endophytic fungi   * B. subtilis As
with antibacterial    * E. coli As 1.355
activity              * S. aureus As 1.72.

24 endophytic fungi   * B. subtilis (ATCC
(with moderate        6633)
antibacterial         * M. luteus (ATCC
activity)             10240)
                      * S. aureus (ATCC
                      * E. coli (ATCC
                      * P. aeruginosa (ATCC

Unidentified          * E. coli

fungus strain 6650

Chlohdium sp.         * E. coli
(J.F.H.               * Bacillus sp.
Beyma)W. Gams &       * P. aeruginosa
Holubova-Jchova       * P. fluorescens

Altemaria sp. strain  * E. coli
JCM9.2                * E.faecium
                      * Emerococcus cloacae
                      * S. aureus
                      * S. pneumonia
                      * P. aeruginosa
                      * K. pneumonia

Micwdiplodia sp.      * E. coli

strain 7092

Microsphaeropsis sp.  * E. coli
strain 8875

Microsphaeropsis sp.  * E. coli

strain 7177

Twenty-nine           * E. coli,

unidentified          * S. aureus
endophytic fungal     * B. subtilis
strains               * P. aeruginosa
                      * Salmonella

F. solani 2,          * E.coli (As 1.355)

Bionectria sp 2. 15   * S. aureus (As 1.72)
other strains         * B. subtilis (As

Trichoderma           * S. aureus

ovalisporum PRE-5     * B. cereus
                      * M. luteus
                      * E. coli

Xylaria sp. NCY2      * E. coli ATCC 25922.

                      * B. subtilis ATCC
                      * S. aureus ATCC

Endophytic fungal     Type of test                 Reference

Phomopsis isolate     Disk diffusion assay         Horn et
MF6031                                             al.

Unidentified          Agar diffusion method        Brady et
endophytic fungus                                  al.
CR115                                              (2000).
                                                   Singh et
                                                   Brady et

Colletotrichum sp.    Paper-disk assay on LB       Lu et al.

Guignardia sp.        Microtiter plate assay       Rodrigues
                                                   et al.

Colletotrichum        Paper-disk assay on LB       Zou et
gloeosporioides                                    al.
13 isolates of

                      Bioautographic TLC           Corrado
                      agar-overlay assay           And

Phomopsis sp.                                      Rodrigues


Periconia sp.OBW-15   Twofold microtiter broth     Kim et

                      dilution method              al.

Rhizoctonia sp.       Agar dilution method         Ma et
strain Cy064                                       al.(2004)

Fusarium sp. IFB-121  Liquid dilution method       Shu etal.

Phornopsis sp.        Serial dilution assay        Weber et
strain                                             al.
E02018                                             (2004)

Aspergillus sp.       Disk diffusion method        Li et
strain CY725                                       al.(2005)

Ampe/omyces sp.       Serial dilution assay        Aly et

Phoma sp. NG-25       Disk diffusion assay         Hoffman


Thielavia             Disk diffusion method        Kusari et
subthermophila                                     al.(2008)

Xylaria sp. YX-28     Twofold serial dilutions     Liu et

                      method                       al.

Pichia                A modified                   Zhao and
guilliermondii        micro-dilution-colorimetric  Zhou
Ppf9                  assay, using the             (2008)
                      chromogenic                  Zhao et
                      MTT                          al.

15 endophytic fungi   Agar diffusion test          Gong and
with antibacterial                                 (2009)

24 endophytic fungi   Disc diffusion method        Hazalin
(with moderate                                     Et
antibacterial                                      al.
activity)                                          (2009)

Unidentified          Disc diffusion method        Hussain

Ascomycete                                         al.
endophytic                                         (2009)
fungus strain 6650

Chlohdium sp.         Microdilution method in a    Kharwar
(J.F.H.                                            Et
Beyma)W. Gams &       96-well microplate           al.
Holubova-Jchova                                    (2009)

Altemaria sp. strain  Dilution assay               Kjer et
JCM9.2                                             (2009)

Micwdiplodia sp.      Agar diffusion assay         Krohn et
strain 7092                                        al.

Microsphaeropsis sp.  Agar diffusion assay         Krohn et
strain 8875                                        al.(2009)

Microsphaeropsis sp.  Agar diffusion assay         Krohn et
strain 7177                                        al.

Twenty-nine           Agar diffusion test          Chen et

unidentified                                       al.
endophytic fungal                                  (2010a)

F. solani 2,          Paper-disc diffusion method  Chen et

Bionectria sp 2. 15                                (2010b)
other strains

Trichoderma           Paper-disc diffusion method  Dang et
ovalisporum PRE-5                                       al.

Xylaria sp. NCY2      Microdilution method in a    Hu et al.
                      96-well microplate           (2010)

Antibacterial substances isolated from endophytic fungi

The number of secondary metabolites produced by endophytic fungi is larger than that of any other endophytic microorganism class. This might partially be a consequence of the high frequency of isolation of endophytic fungi from plants (Zhang et al. 2006). Due to the same reason, some fungal genera seem to have a higher frequency of isolation and therefore a relatively greater chance of discovering an antibacterial substance produced by its belonging species.

The discovery of an antibacterial effect of a crude extract of the culture broth or the mycelium is the first of the steps needed for the discovery of a new antibiotic. It often happens that the individual substances comprising a crude extract do not have a potent antibacterial activity themselves, but act synergistically in a mixture. The identification and structure elucidation of the most potent metabolite is essential in the development of a new antibiotic that would potentially be used in therapy.

Two new 10-oxo-10H-phenaleno[1,2,3-de]chromene-2- carboxylic acids, xanalteric acids I and II (Fig. 1), and 11 known secondary metabolites were obtained from extracts of the endophytic fungus Alternaria sp., isolated from the mangrove plant Sonneratia alba collected in China (Kjer et al. 2009). The two new compounds xanalteric acids I and II showed weak antibacterial activity against Staphylococcus aureus with MIC values of 250 and125 [micro]g/ml, respectively. Altenusin (Fig. 1) exhibited broad antimicrobial activity against several resistant pathogens with MIC values in the range of 31.25-125 [micro]g/ml.

In a more recent study of antimicrobial activity of crude extracts from mangrove fungal endophytes Buatong et al. (2011) tested a total of 385 extracts from 150 fungal endophytes with an antimicrobial screening test (a colorimetric microdilution method). They isolated endophytic fungi from leaves and branches 12 mangrove species (Aegiceras corniculatum, Avicennia alba, Avicennia officinalis, Bruguiera gymnorrhiza, Bruguiera parviflora, Lumnitzera littorea, Rhizophora apiculata, Rhizophora mucronata, Son neratia caseolaris, Scyphiphora hydrophyllacea, Xylocarpus granatum and Xylocaipus inoluccensis)collected from mangrove areas in the south of Thailand in Satun, Songkhla, Surat Than i and Trang Provinces. They prepared crude ethyl acetate extracts from the culture broth and ethyl acetate and hexane extracts from the fungal mycelia and determined their MIC and minimal bactericidal concentrations ( MBC) against human pathogenic bacteria. Ninety-two isolates produced inhibitory corn-pounds. Most of the extracts (28-32%) inhibited S. aureus (MIC/MBC 4-200/64-200 [micro]/m1). Only two extracts inhibited P. aeruginosa (MIC/MBC 200/>200 [micro]g/ml) and none of the extracts inhibited E. coli. The most active fungal extracts were from six genera, Acremonium, Diaporthe, Hypoxylon, Pestalotiopsis, Phomopsis, and Xylaria. Phomopsis sp. MA194 isolated from Rhizophora apiculata showed the broadest antimicrobial spectrum with low MIC values of 8-32 [micro]/m1 against Gram-positive bacteria.

Chromatographic separation of extracts of cultures grown in liquid or on solid rice media of the endophytic fungi Ampelomyces sp. isolated from the medicinal plant Urospermum picroides yielded 14 natural products that were identified based on their [1.sup.H] and [13.sup.C] NMR as well as mass spectra and comparison with previously published data. 3-O-methylalaternin, obtained from the extracts of Ampelomyces sp. grown in liquid culture, and altersolanol A, form the fungus grown on solid rice medium, both displayed antimicrobial activity against the Gram-positive pathogens. 3-O-methylalaternin showed activity with a MIC of 12.5 [micro]/ml against Staphylococcus epidermidis, S. aureus, Enterococcus faecalis. Alter-solanol A featured a MIC value of 12.5 [micro]g/ml against S. epidermidis and E. faecalis, and 25 [micro]/ml against S. aureus (Aly et al. 2008). An earlier report by Yagi et al. had already revealed that altersolanol A inhibits the growth of Gram-positive bacteria and Pseudomonas aeruginosa IFO 3080 when tested using the broth dilution method (Yagi et al. 1993).

Aspergillus sp. HAB1OR12 was isolated from the root of Garcinia scortechinii, a small tree distributed throughout Malaysia which is often used by local people for peptic ulcer and postpartum care (Ramasamy et al. 2010). Xanthones isolated from the host plant G. scortechinii have been found previously to inhibit methicillin-resistant Staphylococcus aureus (MRSA) (Sukpondma et al. 2005). The antimicrobial activity of the crude ethyl acetate extract of the culture agar was tested against Bacillus subtilis, Escherichia coli, Micrococcus luteus and S. aureus using a disc diffusion method. Extract of the HAB1OR12 was able to significantly (p < 0.05) inhibit B. subtilis (24 mm) and S. aureus (23 mm), better than M. luteus (18 mm). The positive controls (ampicillin, ceftriaxone, cephalexin and gentamicin) showed inhibitory activity as expected, resulting in inhibition zones with diameters ranging from 11 to 25 mm. The antibacterial effect of 1-1AB1OR12 was similar to that of the control antibiotics when tested against M. luteus and S. aureus and significantly (p< 0.05) greater than gentamicin against B. subtilis and E. coli, and cephalexin against B. subtilis.

Kharwar et al. reported a highly functionalized naphthaquinone javanicin (Fig. 1), with promising antibacterial activity, from an endophytic Chloridium sp. that was isolated from the surface treated root tissues of Azadirachta indica A. Juss (Kharwar et al. 2009). In their antibacterial test, javanicin was active against E. coli and Bacillus sp. at a higher MIC value of 4014/m1. The bacteria that were the most sensitive to javanicin (2 p.g/ml) were P. aeruginosa and P. fluorescens. This could be an indicator of the selective antibacterial activity of javanicin, but it should be confirmed with additional testing.

Arivudainambi etal. have isolated a new endophytic fungus Col-letotrichum gloeosporioides from the medicinal plant Vitex negundo L. and tree different extracts (hexane, ethyl acetate and methanol) were screened for their antibacterial activity against methicillin-, penicillin- and/or vancomycin-resistant clinical strains of S. aureus (Arivuclainambi et at. 2011 ).The results of the disc diffusion method showed that methanol extract had an effective antimicrobial activity against all tested bacteria. The methanol extract produced a maximum inhibition zone of 21.6 mm against S. aureus, 19.6 mm against B. subtilis, 18.3 mm against E. coli and 18.6 mm against P. aeruginosa. In contrast, the hexane extract had no inhibitory effect against all the tested organisms. The ethyl acetate extract exhibited moderate antimicrobial activity against all the tested microorganisms. More importantly, they also tested the extracts on 10 different clinical isolates of resistant S. aureus. The hexane and ethyl acetate fungal extracts had no antibacterial activity against multidrug-resistant S. aureus strains. But the methanol extract of C. gloeosporioides showed an effective antibacterial activity against S. aureus strains. A maximum inhibition zone of 20 mm was observed against S. aureus strain 9 which was resistant to vancomycin, methicillin and penicillin.

It is also fairly common to find the same endophytic fungi in different host plant species. Colletotrichum gloeosporioides is an example of this. The same endophytic fungus was isolated from the stem of Artemisia mongolica (Fisch. ex Bess.) Nakai. Antimicrobial bioassay revealed that colletotric acid (Fig. 1), isolated from the culture liquid, was inhibitory to the bacteria B. subtilis, S. aureus, and Sarcina lutea with minimal inhibitory concentrations (M1Cs) of 25, 50, and 50 respectively (the MICs of ampicillin against these microorganisms: 0.05, 0.5, and 0.01 lig/m1) (Zou et al. 2000). What is interesting is that colletotric acid was purified from the ethyl acetate extract of the culture broth, and Arivudainambi et al. also reported moderate inhibitory activity of the ethyl acetate extract.

Similarly, Lu et al. reported that the metabolites of enclophytic fungus Colletotrichum sp. isolated form Artemisia annua had strong antimicrobial activity against the bacteria B. subtilis, S. aureus, S. h./tea and Pseudomonas sp. (Lu et al. 2000). With the use of a combination of spectroscopic methods (IR, MS, 1H and 13C NMR) they elucidated the structure of tree new metabolites: 6-isoprenylindole-3-carboxylic acid; 3b,5a-clihydroxy-6b-acetoxy-ergosta-7,22-diene and 3b,5a-dihydroxy-6b-phenylacetyloxy-ergosta-7,22-diene and also isolated tree more substances with known structures: 3b-hydroxy-ergosta-5-ene; 3-oxo-ergosta-4,6,8(14),22-tetraene and 3b-hyclroxy-5a,8a-epidioxy-ergosta-6,22-diene. All of them exhibited antimicrobial activities with M1Cs ranging from 25 to 75 [micro],g/ml.

Endophytic fungus from the genus Colletotrichum was isolated among others from healthy tissues of Lippia sidoides, a medicinal plant used as an antiseptic in the northeast of Brazil (de Siqueira et al. 2011). From 480 fragments of leaves and stems of L. sidoides, a total of 203 endophytic fungi were isolated, representing 14 species belonging to the groups Ascomycota, Coelomycetes and Hyphomycetes. Colletotrichum gloeosporioides was the most frequently isolated, followed by Alternaria alternata, Guignardia bid-welli and Phomopsis arched. All the isolated fungal strains were submitted to an antimicrobial assay on solid medium (Ichikawa et al. 1971). The endophytic fungi with antimicrobial activity were limited to four species: A. altemata, P. archeri, C. gloeosporioides and Drechslera dematioidea with inhibition zones ranging from 17 to 25 mm against S. aureus and Bacillus subtilis.

In the investigation of the endophytic fungi associated with medicinal plants Dendrobium devonianum and D. thyrsifloruin collected in Vietnam 30 endophytic fungi were isolated from 100 tissue segments (50 segments from stern and root each) of D. devo-nianum, while 23 isolates were gained from D. thy rsiflorum. The antimicrobial activity of all 53 endophytic fungi was evaluated against six human pathogens (Xing et al. 2011). Antimicrobial activity of the ethanol extract of the fungal fermentation broth at a concentration of 10011g/disk was tested with the agar diffusion method against S. aureus, E. coli, and B. subtilis. Epicoccum from root of D. thyrsiflorum exhibited an inhibitory activity against S. aureus, E. coli, and B. subtilis. The emphasis was put on the ethanol crude extract of Epicoccum nigrum that displayed the strongest antagonistic effect on S. aureus even superior to ampicillin. Four isolates in D. devonianum exhibited antagonistic effects against more than one pathogenic microorganism out of which Phoma showed greatest inhibitory activity against E. coli. Seven endophytes from D. thyr-siflo rum were active. Phoma from root of D. thy rsiflorum exhibited strongest activity against B. subtilis and slightly inhibited S. aureus as well. Fusarium tricinctum from D. thyrsifiorum showed antagonistic actions against E. coli and B. subtilis. The antibacterial potential of Epicoccum sp. was noted back in 1978 when Baute et al. studied a strain 751-5 of Epicoccum nigrum, which was isolated from atmosphere in 1958 at the Centre de Recherches de Bioclimatolo-gie of Pau (France). It should be noted that in this case the strain of E. nigrum was not endophytic, but nonetheless, the research group successfully isolated epicorazine A and B as the active antibacterial substances from the chloroformic extract of the culture broth (Baute et at. 1978; Deffieux et al. 1978a,b).

Adding to the already broad palette of structural diversity of metabolites produced by Fusarium endophytes, Shu et al. have isolated two antibacterial cerebrosides, designated cerebroside 1 and 2, from chloroform-methanol (1:1) extract of Fusarium sp. IFB-121, an enclophytic fungus in Quercus variabilis. The cerebrosides were strongly active against B. subtilis, E. coil, and P. fluorescens, with the MICs of cerebroside 1 being 7.8, 3.9, and 7.814/ml, and that of cerebroside 2 being 3.9, 3.9, and 1.9 lig/m1, respectively. The MICs of the amikacin that was used as a positive reference against the three bacteria were 0.45,3.9, and 3.9 jig/ml, respectively (Shu et al. 2004).

Investigations on the antimicrobial activities of endophytic fungi in Dendrobium loddigesil Rolfe were carried out by Chen et al. (2010b). They isolated 48 fungal cultures from 120 healthy samples of D. loddigesii and grouped them into 18 identified genera, of which Fusarium and Acremonium represented 21 of the total isolates and were the dominant genera in the plants. Chaetomella, Cladosporium, Nigrospora, Pyrenocha eta, Sirodesmium, and Thielavia were found in Dendrobium for the first time. The ethyl acetate extract of the culture filtrate of 17 (35.4%) isolates, all obtained from roots, showed antimicrobial activity against one or more of the human pathogenic microbes. Surprisingly, none of the tested extracts exhibited inhibitory activity against E. coli. When tested on S. aureus, the most active were the strains designated F. solani 2 and Bionectria sp 2., with the diameter of inhibition zone of 22.7 [+ or -] 0.7 mm and 24.0 [+ or -] 0.6 mm, respectively. Accounting for almost half of the active isolates, Fusarium was the predominant genus in antimicrobial isolates.

In a study by Sim et al. a total of 24 endophytic fungi that comprised 10 different genera were successfully recovered from the isolation process, which included four isolates from Garcinia man-gostana, and 20 from Garcinia parvifolia, selected randomly from the fruit farm of Sungai Rengit Village, Johor, Malaysia (Sim et al. 2010). The antibacterial activity of the filtered broth suspension of all the isolated endophytic fungi was measured using a well diffusion method. Eleven isolates (45.8%) displayed antimicrobial activity against at least one test microorganism with inhibition zones that ranged from 5 to 12 mm. Two isolates, 56 GP and 190 GP, identified as Fusarium equiseti and Guignardia vaccinii, respectively, possessed the most antibacterial activities.

Dragon's blood is a deep red resin, which has been used as a famous traditional medicine since ancient times in many countries. In China, the red resin of Dracaena cambodiana Pierre ex Gagnep. (Agavaceae) is used as the main source of Chinese dragon's blood. The other very important source is Aquilaria sinensis (Lour.) Gilg. (Thymelaeceae). Gong and Guo studied the endophytic fungi of these two plants and obtained 300 isolates. 172 were from Dracaena cambodiana and 128 from Aquilaria sinensis. 21 isolates showed antimicrobial activity, however, none of these isolates was active against E. coli, and only 15 were active against B. subtilis and/or S. aureus. Out of those 15, nine isolates were a Fusarium sp. and active against B. subtilis with the inhibition zone diameter in the range of 10.33-22.00 mm. The isolate DC-2-32, identified as Fusarium sp. 1, exhibited strong antibacterial activity with a 22 mm inhibition zone diameter to B. subtilis, and should be considered for further investigation. Moreover, some of the isolates exhibited broad spectrum antimicrobial activity and the inhibition zones ranged from 7 to 27 mm. The active isolates were identified to 17 taxa. Just as in the study by Chen et al. (2010b), in this one also Fusarium spp. was the most dominant genera in two plants and showed the most potent antimicrobial activity (Gong and Guo 2009).

The same research group investigated samples containing Dragon's blood from D. cambodiana and D. cochinchinensis and a total of 49 fungal isolates were obtained, of which 43 isolates belonged to 18 genera, and another six were unidentified fungi. Fusarium was again the dominant genus isolated from D. cambodiana, comprising 14 isolates out of 26 (Cui et al. 2011). Twenty isolates displayed antimicrobial activity against at least one pathogenic microorganism. The inhibition zones ranged from 8.0 mm to 30.9 mm. Among all the isolates, 14.3%, 16.3% and 18.4% of endophytic fungi inhibited E. coli, B. subtilis and S. aureus, respectively. Isolate YNDC07 exhibited significant antibacterial activity against S. aureus with a diameter of the inhibition zone greater than 17 mm. Isolates YNDC05 and YNDC11 also exhibited strong activities against B. subtilis and E. coli, respectively.

In Indonesia, the indigenous communities have been using Garcinia mangostana plant for the treatment of various infectious diseases. Guided by the possibility that the endophytic fungi residing within part of plants could also produce metabolites similar to the activity of their respective hosts, a screening of the antibacterial activity of endophytic fungi isolated from surface sterilized leaves and small branches of Garcinia mangostana was conducted (Radji etal. 2011). During this study, 24 fungal isolates were recovered and the crude ethyl acetate extracts of all the endophytic fungi were tested for their antibacterial activity against S. aureus, B. subtilis, E. coli, P. aeruginosa, S. typhi and M. luteus. Antibacterial activity was determined using the disc diffusion method. Out of 24 isolates, 10 isolates could inhibit some tested human pathogenic bacteria used in this study. Each of them displayed antimicrobial activity against at least one test microorganism with inhibition zones that ranged from 6.5 to 14.7 mm. More than half of the active isolates inhibited strains of Gram-positive bacteria better than Gram-negative bacteria. The strongest antibacterial activity against selected bacteria was displayed by isolate RGM-02. The inhibition zones against B. subtilis, S. aureus, and M. luteus were 14.7, 12.9 and 13.5 mm, respectively. Surprisingly, the ethyl acetate extract from isolate RGM-02 had MIC values of 25 [micro]g/m1 against M. luteus and 25[micro]g/m1 against S. aureus, which was only two and four times higher than that of amoxicillin (MIC 12.5 and 6.25 pg/ml), respectively. Based on 18S ribosome RNA sequence analysis, the isolate RGM-02 was identified as Microdiplodia hawaiiensis CZ315.

Krohn et al. have reported the discovery of several new aromatic, hydrogenated, and structurally unique ring-extended xanthones from different enclophytic fungi. Three new metabolites, microsphaeropsones A-C with a unique oxepino [2,3-b]chromen-6-one (ring-enlarged xanthone) skeleton, citreorosein and an enone (oxidized microsphaeropsone A) were isolated from the endophytic fungus Micros phaeropsis species. From Microsphaeropsis species, large amounts of fusidienol A and known aromatic xanthones were isolated and from Microdiplodia sp. 3,4-dihydroglobosuxanthone A was purified. Preliminary studies by agar diffusion assay showed that those metabolites have antibacterial activity against E. coli (Krohn et al. 2009).

In 2004, fusicoccane diterpenes. named periconicins A and B (Fig. 1), were isolated from an endophytic fungus Periconia sp., collected from small branches of Taxus cuspidata (Kim et al. 2004). They were purified from the ethyl acetate extracts of the broth, which were active in the antibacterial assays. Periconicin A exhibited significant antibacterial activity against B. subtilis, S. aureus, Klebsiella pneumoniae and Salmonella typhimurium with MIC in the range of 3.12-12.5 lig/ml, in comparison to gentamicin, with the MIC in the range of 1.56-12.514/ml. Periconicin B exhibited modest antibacterial activity against the same strains of bacteria with MIC in the range of 25-5014/ml. Both periconicins A and B were inactive against E. coli.

Phomodione, an usnic acid derivative, was isolated from culture broth of a Phoma species, discovered as an endophyte on a Guinea plant (Saurauia scaberrinae). In addition to phomodione, known compounds with antibiotic activity, usnic acid and cercosporamide, were also found in the culture medium. Phomodione exhibited a MIC of 1.6 vtg/m1 against S. aureus using the disk diffusion assay. None of the compounds was effective against E. coli at 500 [micro]g or lower, but MICs of all three compounds were approximately the same on S. aureus, indicating that these compounds may be much more effective against gram positive bacteria (Hoffman et al. 2008).

Rodrigues et al. have studied the endophytic fungi Guignardia, Pestalotiopsis guepinii and Phomopsis sp. isolated from Spondias mombin L. (Anacardiaceae), which has been used in Brazil in traditional medicine because of its antimicrobial properties. Only the culture broth ethyl acetate extract of Guignardia was active against S. aureus and E. coli (Rodrigues et al. 2000). HPLC analysis showed that this crude extract contained at least five metabolites, and in following research they were able to isolate guignardic acid, a new type of secondary metabolite, but have not reported on its individual antibacterial activity (Rodrigues-Heerklotz et al. 2001). Later, in 2004, Corrado and Rodrigues examined the crude extract of cultures of 13 fungal strains identified as Phomopsis sp. and isolated as endophytes from the leaves of Aspidosperma tomentosum and twigs of Spondias mombin for their antibacterial activities. The screening was conducted using the bioautographic TLC agar-overlay technique against bacteria (E. coli, P. aeruginosa, S. aureus). Four strains isolated from Aspidosperma tomentosum designated: IOC 4240, IOC 4239,10C 4242 and IOC 4243 had a 4-5 mm zone inhibition against E. coli and P. aeruginosa, but none against S. aureus. Two of the strains from Spondias mombin, named IOC 4236 and IOC 4235, were active against E. coli and S. aureus while the third, IOC 4237 was able to inhibit the growth of P. aeruginosa.

Phomopsichalasin (Fig. 1), a metabolite from an endophytic Piromopsis sp., represents the first cytochalasin-type compound with a three-ring system replacing the cytochalasin macrolide ring. This metabolite exhibited antibacterial activity in disk diffusion assays (at a concentration of 4 ilgidisk) against B. subtilis (12-mm zone of inhibition) and S. aureus (8-mm zone of inhibition) (Horn et al. 1995).

Dai et al. screened the endophytic fungi from four medicinal plants of the family Euphorbiaceae (Sapium sebiferum, Euphorbia pekinensis, E. hetioscopia and Bischofia polycarpam) and detected the antibacterial activity of these strains (Dai et al. 2006). Their results indicated that 11 strains of a total of 43 belonged to Alternaria spp., Fusarium spp., Chaetomium spp., Coniothyium spp. and Phomopsis spp. and showed antibacterial activity against tested bacteria such as S. aureus and B. subtilis.

Phomol (Fig. 1), a novel antibiotic, was isolated from the fermentation broth of Phomopsis sp. strain E02018 in the course of a screening of endophytic fungi from the medicinal plant Erythrina crista-galli (Weber etal. 2004). In the serial dilution assay it showed only moderate antibacterial activity against Arthrobacter citreus, Corynebacterium insidiosum and Pseudomonasfluorescens and it was not active against E. coli or B. subtilis.

As part of a program on the isolation of biologically active compounds the research group of prof. Krohn has investigated a number of metabolites from Phomopsis sp. (internal strain no. 8966), isolated from the plant Notobasis syriaca (Hussain et al. 2011). The culture medium of the endophyte was extracted and fractionated with silica gel column chromatography and TLC to give the following pure compounds: phomosine K, a new phomosine derivative and six known compounds: phomosine A, phenylalanine amide, 2-hydroxymethy1-413,5cx,63-trihydroxycyclohex-2-en, ( - )-phyllostine, (+)-epiepoxydon, and (+)-epoxydon monoacetate. Preliminary studies showed that phomosine A had strong antibacterial activity the MICs against E. coli and Bacillus megaterium were determined to be 12.5 [micro]/ml.

The same group has also isolated an another interesting group of secondary metabolites with antibacterial activity from a different Phomopsis sp. isolated from Cistus salvifolius (internal strain 7852) (Hussain et al. 2012). The mycelium was extracted with ethyl acetate and the crude extract further fractionated on a silica gel column to yield a crude mixture containing pyrenocines J-M. Further silica column chromatography or preparative TLC gave the pure compounds. Solutions of individual pyrenocines in acetone were tested using the agar diffusion test for antibacterial activity against E. coli and B. megaterium. Against E. coli all of the tested pyrenocines showed moderate antibacterial activity with zone of inhibition radiuses ranging from 5 to 10 mm. Penicillin and tetracycline were used as positive controls and had zones of inhibition with much higher radiuses (14 and 18 mm, respectively against E. coli). Against B. megaterium none of the pyrenocines showed complete inhibition of growth, though partial inhibition of growth was evident.

Zao et al. have investigated the plant Paris polyphylla var. yun-nanensis (Franch) Hand.-Mazz. (Trilliaceae) that has been used in traditional Chinese medicine (TCM) for treatment of injuries from falls, fractures, contusions, bleeding and immunity disorders (Zhao et al. 2010; Zhao and Zhou 2008). The crude n-butanol extracts of sixteen endophytic fungi isolated from the rhizomes of Paris poly-phylla var. yunnanensis were preliminarily investigated for their antibacterial activity by the agar well diffusion assay and a modified broth dilution test. Eight endophytic fungi (i.e. Ppfl, Ppf2, Ppf4, Ppf8, Ppf9, Ppf10, Ppf14 and Ppf15) showed strong antibacterial activity against the test bacteria (B. subtilis, S. haemolyticus, E. coli). MIC values of the extracts were between 0.0625 and 2 mg/mi. The endophytes with better antibacterial activity were identified by morphological characters and internal transcribed spacer (ITS) rRNA gene sequence analysis (Zhao and Zhou 2008). After determining the antibacterial activity of the crude extract, they proceeded to the bioassay-guided fractionation to determine the antimicrobial components produced by the endophytic fungus Pichia guilliermondii Ppf9. They identified four compounds as follows: ergosta-5,7,22-trienol; 5a,8a-epidioxyergosta-6,22-dien-313-ol; ergosta-7,22-dien-313,5m63-triol, and helvolic acid (Zhao et al. 2010). The antimicrobial activities of these compounds were further evaluated by micro dilution colorimetric and spore germination assays. The antimicrobial activity assay indicated that helvolic acid (Fig. 1) could be the main antimicrobial component in endophytic fungus P. guillierniondii Ppf9, as this compound exhibited the strongest antibacterial activity on E. coli, B. subtilis, S. aureus and S. haernolyticus, with MIC values of 3.13, 3.13, 50 and 6.25 [micro],g/ml, respectively. Its antibacterial activity was close to or a little stronger than that of streptomycin sulfate (the positive control). Among the three isolated steroids 5a.,8a-epidioxyergosta-6,22-dien-313-ol exhibited relatively strong antimicrobial activity and the authors speculated that the peroxide bridge between C-5 and C-8 positions may be crucial for the antimicrobial activity.

A strain PRE-5 was isolated from Panax notoginseng, collected in Yunnan Province, China, and identified as Trichoderma ovalisporum. This strain showed antibacterial activity, which is why the culture broth of the strain was further characterized and the antibacterial activity of the individual compounds from this fungal strain tested (Dang et al. 2010). Five compounds were isolated from the culture broth: koninginin A (Fig. 1), (E)-2,3-dihydroxypropyl octadec-9-enoate, shikimic acid, cytosine ribonucleoside and a compound considered to be adenine ribonucleoside. Strain PRE-5 showed obvious antibacterial activity against S. aureus, B. cereus, M. luteus, and E. con. In the paper-disc diffusion antimicrobial assay, shikimic acid showed moderate antibacterial activity against S. aureus, B. cereus, M. luteus and E. coli with diameter of the resulting bacteria-free zone 10 mm, 9 mm, 7 mm and 11 mm, respectively. The rest of the isolated compounds did not show any obvious activity against the tested strains.

Many bioactive compounds, including antifungal agents, have been isolated from the genus Xylaria residing in different plant hosts, The bioactive compound isolated from the culture extracts of the endophytic fungus Xylaria sp. YX-28 isolated from Ginkgo biloba L. was identified as 7-amino-4-methylcoumarin (Liu et at. 2008). Its antimicrobial activity was determined by the agar-well diffusion method and the M1Cs were determined. The compound showed strong antibacterial activity against S. aureus (MIC 16 [micro]g/m1), E. coli (MIC 10 [micro]g/ml), Salmonella typhia (MIC 20 [micro]g/m1), S. typhimurium (MIC 15 [micro]g/m1), Salmonella enteritidis (MIC 8.5[micro]g/m1), Aeromonas hydrophila (MIC 4[micro]g/ml), Yersinia sp. (MIC Vibrio anguillarum (MIC 25 [micro]g/ml), Shigella sp. (MIC 6.3 [micro]g/m1), and Vibrio parahaemolyticus (MIC 12.5 [micro]g/m1). Most importantly, the obtained MICs were comparable or even lower than those obtained for the positive control antibiotics ampicillin, gentamicin or tetracycline. Another isolate of the endophyte Xylaria sp. NCY2 from Torreya jackii was described by Hu et al. (2010) to produce seven novel polyketides: 1-(xylarenone A) xylariate A, xylarioic acid B, xylariolide A, xylariolicle B, xylariolide C, methyl xylariate C. and xylariolide D and additionally the known taiwapyrone. In an antibacterial assay these metabolites inhibited the growth of E. con. B. subtilis, and S. aureus with MIC values above 10 [micro]g/ml.

Some of the discovered endophytes remain unidentified. As part of a project exploring the endophytic fungi of Costa Rica, fungal extracts were screened for antibiotic activity against drug-resistant strains of S. aureus and E. faecalis. Guanacastepene A, a diterpene with a novel guanacastepane carbon skeleton, was isolated from an unidentified endophytic fungus from the branch of Daphnopsis americana by Brady et al. in 2000 and its structure was determined by X-ray crystallography (Brady et al. 2000). In agar diffusion assays run on bacterial lawns, pure guanacastepene A showed antibiotic activity against methicillin-sensitive and -resistant S. aureus and vancomycin-resistant E. faecalis. Against MRSA 100 [micro]g of guanacastepene A or vancomycin produced 11 and 17 mm zones of growth inhibition, respectively. While vancomycin was ineffective against VREF, guanacastepene A produced a 9 mm zone of growth inhibition. In 2001, several additional guanacastepenes B-0 have been isolated from the same fungus and structurally characterized (Brady et al. 2001). A setback in the exploitation of this metabolite as a new antibacterial agent is the haemolytic activity against human erythrocytes (Singh et al. 2000). Its promising profile against MRSA and VREF has stimulated an intensive world-wide search for synthetic and naturally occurring analogues.

An unidentified ascomycete fungus was isolated from Melilotus dentatus (Hussain et al. 2009), and the ethyl acetate extract of the culture broth was chromatographed on silica gel to give four pthalides (7-hydroxyphthalide, 4-hydroxyphthalide, 5-methoxy-7-hydroxyphthalicle, 5,7-dihydroxyphthalide), two isocoumarins ((3RAR)-cis-4-hydroxymellein and (3R,4R)-cis-4-hydroxy-5-methylmellein) and two steroids (ergosterol and 5ct,8a-epidioxyergosterol). 4-Hydroxyphthalide and 5- methoxy-7-hydroxyphthalide were active against E. coli.

In a study of endophytic fungi from Malaysian plant species, a total of 300 endophytes were isolated from 43 plants (Hazalin et al. 2009). Ardisia colorata was found to host the highest number of endophytes (14 isolates), followed by Molineria latifolia (13 isolates) and Zingerberaceae sp., KT43 (13 isolates). The ethyl acetate extracts of the ground mycelium and culture agar of all the isolated endophytes were tested against B. subtilis, M. luteus, S. aureus, E. coli and P. aeruginosa. Out of the 300 isolates tested, only 24 displayed antibacterial activity against at least one test microorganism with inhibition zones of 7-8 mm and none of the isolates were as potent as gentamicin sulfate.

Endophytic fungi producing metabolites effective against Helicobacter pylori

Part of the research is also focused on the search of new antibacterial agents for the therapy of Helicobacter pylori infections. Ma et al. have investigated the methanol extract of the solid-substrate culture of Rhizoctonia sp. found in Cynodon dactylon (Poaceae) (Ma et al. 2004). With fractionations directed by anti-Helicobacter pylori test, four compounds were characterized from the extract: rhizoc-tonic acid (Fig. 1), monomethylsulochrin (Fig. 1), ergosterol and 3b,5a,6b-trihydroxyergosta-7,22-diene. All four metabolites were subjected to a more detailed in vitro assessment of their antibacterial action against five clinically isolated and one reference H. pylori strain. The M1Cs of the compounds against all of the five clinical and a reference strain were in the range from 10.0 to 30.0 ii.g/m1 while the MIC of ampicillin used as the positive control against these strains was 2.0 pg/ml (Ma et al. 2004). Their search for a more potent product continued and a year later, the same research group isolated 32 endophytic fungi from the same medicinal herb (Li et al. 2005). The endophytic fungi were then grown in in vitro culture, and the ethyl acetate extracts of the cultures were examined for anti-H. pylori activity. As a result, a total of 16 endophyte culture extracts were identified as having potent anti-H. pylori activities. Subsequently, a detailed bioassay-guided fractionation of the extract of the most active endophyte (strain number: CY725) identified as Aspergillus sp., was performed. Four anti-H. pylori secondary metabolites were identified to be helvolic acid, monomethylsulochrin, ergosterol and 3b-hydroxy-5a,8a-epidioxy-ergosta-6,22-diene with corresponding MICs of 8.0, 10.0, 20.0 and 30.0 pgJml, respectively. The MIC of ampicillin co-assayed as a reference drug against H. pylori was 2.011g/ml. Furthermore, preliminary examination of the antimicrobial spectrum of helvolic acid, the most active anti-H. pylori metabolite characterized from the endophyte culture, showed that it was inhibitory to the growth of Sarcina lutea. and S. aureus with MICs of 15.0 and 20.0 [micro]g/ml, respectively.

Interestingly, the most recent report from the same research group again features monomethylsulochrin and rhizoctonic acid, as well as a new fungal toxin named guignasulfide, with very similar MIC values as the compounds responsible for the anti-H. pylori activity of a methanol extract. This time the methanol extract was prepared from the solid-substrate culture of Guignardia sp. IFB-E028 isolated from healthy leaves of Ho pea hainanensis Merrill & Chun (Dipterocarpaceae) (Wang et al. 2010). The isolated metabolites were moderately inhibitory on the growth of H. pylori with the corresponding MIC values of 28.9[+ or -]0.1, 60.2[+ or -]0.4, and 42.9[+ or -]0.5 [micro]M. For comparison, the MIC of ampicillin co-assayed as a positive reference was 5.4[+ or -] 0.2 [micro]M. After recalculating, the MICs of monomethylsulochrin and rhizoctonic acid are around 10 and 20 [micro]g/ml respectively, which is consistent with their previous report. Although the isolated substances do have antibacterial activity, their MICs are higher than that of ampicillin. Perhaps, with some effort from pharmaceutical chemists, certain structural modification would be able to improve their antibacterial potency.

Endophytic fungi as producers of the same metabolites as the host plant

Some endophytes can produce the same rare and important bioactive compounds originally characteristic of the host plant (Tan and Zou 2001). This ability is of great importance in that it provides an alternative strategy for reducing the need to harvest slow-growing and possibly rare plants and also help to preserve the world's ever diminishing biodiversity. Moreover, the production of a high value phytochemical by exploiting a microbial source is easier and more economical and it leads to increased availability and the reduced market price of the product (Strobel et al. 2004). One of the most frequently mentioned is the taxol producing endophytic fungus, but examples of endophytic fungi producing substances with antibacterial activity, originally found in host plants have also been discovered.

Kusari et al. have isolated the endophytic fungus designated INFU/Hp/KF/34B and later identified as Thielavia subthermophila from Hypericum perforatum and studied the production of hypericin, a naphthodianthrone derivative, and its precursor, emodin (Kusari et al. 2008, 2009). Both compounds demonstrated antimicrobial activity against several bacteria and fungi, including S. aureus ssp. aureus, K. pneumoniae ssp. ozaenae, P. aeruginosa, Salmonella enterica ssp. enteric, and E. coli (Kusari et al. 2008).

Eucommia ulmoides Oliver is a traditional medicinal plant used in China, and it is one of the main sources of chlorogenic acid. This natural medicinal resource is in short supply because of the over-collection of the wild plant, which is now protected in China Chen et al. reasoned that by isolating an endophytic fungus from Eucommia ulmoides which would be able to produce the same secondary metabolite as its host plant, they would protect the plant from extinction and find an alternative way to produce its active constituents to satisfy the demand. They carried out a study to isolate endophytic fungi from Eucommia ulmoides Oliver and to find out whether any of these fungi can produce chlorogenic acid (Chen et al. 2010a).

Twenty-nine endophytic fungal strains were isolated on the basis of morphology, and they were divided into six groups (N, B, S, C, A, E). Due to the antimicrobial activity of chlorogenic acid they discriminated the isolated endophytic fungi as potential producers of chlorogenic acid based on the antibacterial activity of their extracts. Most of them were positive for antibacterial activity and were analyzed by HPLC, GC-MS, and LC-MS. Chromatographic analysis indicated that strain B5 might be able to produce chlorogenic acid, although the yield was relatively low and was not quite suitable for its production on an industrial scale.


The results reviewed in this article provide the information about the strains of endophytic fungi whose crude extracts should be studied in further detail. Antibacterial activity is most frequently detected when testing cultures of species belong to genera Fusa-Hum Phomopsis and Phoma. Unfortunately this cannot be assigned to its superior antibacterial activity but rather to the higher frequency of isolation of these fungi in comparison to the rest. Studies in which extract prepared using different solvents are tested show that crude extracts obtained with methanol, ethanol and most often ethyl acetate have antibacterial activity, whereas extracts prepared with nonpolar solvents display no antibacterial activity. The comparison of the intensity of the antibacterial activity between different studies is very difficult, due to the fact that no uniform test strains are used. Perhaps it makes more sense to use clinical isolates and always include positive control to prove the relevancy of the results.

It is important to note that these fungi are capable of producing antibacterial substances in a laboratory and more effort is needed to isolate and purify them in order to determine their structure and mechanism of action. In cases where these natural products have been identified through biological assays, they should be considered as leads, which become candidates for drug development (Molinari 2009). More often than not however, this is where the research comes to a halt, leaving the potential unused. A wide range of additional data about the lead compound needs to be obtained, one of them being the overall toxicity of the substance as well as possible chemical modifications of the natural compounds in order to obtain a more effective antibacterial agent.

The number of antibacterial substances obtained from endophytic fungi is not as large as those obtained from different endophytic bacterial strains, among which Streptomyces sp. seem to be the most productive. There are quite a large number of published articles, not included in this review, dealing with structurally novel metabolites produced by endophytic fungi whose antibacterial potential has not been tested yet. This is also a goal for the future: to perform a comprehensive screening of the antibacterial activity of those metabolites against clinical strains of resistant bacteria.

While the estimated figure of 1.5 million of all fungal species (Hawksworth 2001) is commonly used, it is estimated that there might be 1 million of endophytic fungal species. This seems reasonable if each individual higher plant, of approximately 250,000 different plant species on Earth, hosts an average of four endophytes (Ganley et al. 2004). In the past century, however, only about 100,000 fungal species including endophytic fungus were described (Ganley et al. 2004). Due to the fact that endophytic fungi are south for in plants which have established use in traditional medicine or that grow in areas of great biodiversity, it is obvious that a great deal of potentially useful metabolites await to be discovered. Focusing on the investigation of endophytic fungal diversity, relationships between endophytic fungi and their host plants, seeking for natural bioactive compounds they produce, and improving the productivity of some potential candidates by taking advantage of genetic engineering and microbial fermentation processes might lead to the discovery of the much needed antibiotic for the treatment of infections caused by multidrug-resistant bacteria. It is clear that we still have a very long way to go until the final goal is achieved. However, it is encouraging to know that we are on the right track.

Conflict of interest

No conflict to disclose.


The authors would especially like to thank the Department of Pharmaceutical Biology, Faculty of Pharmacy, University of Ljubljana where both authors were employed during the writing of this article.


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* Corresponding author at: Celica, Biomedical Center, Technology Park 24, Ljubljana, Slovenia. Tel.: +386 40252279.

E-mail address: (N. Radic).

0944-7113/$--see front matter [c] 2012 Elsevier GmbH. All rights reserved.


Natasa Radie (a), (b) Borut Strukelj (c), (d)

(a.) Celica. Biomedical Center, Technology Park 24, Ljubljana, Slovenia

(b.) Laboratory for Neuroendocrinology-Molecular Cell Physiology, Institute of Pathophysiology. Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia

(c.) Department of Pharmaceutical Biology, Faculty of Pharmacy. University of Ljubljana, AS'kerteva cesta 7, Ljubljana, Slovenia d Department of Biotechnology, jatef tefan Institute, jamova 39, Ljubljana, Slovenia
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Title Annotation:Review
Author:Radic, Natasa; Strukelj, Borut
Publication:Phytomedicine: International Journal of Phytotherapy & Phytopharmacology
Date:Nov 15, 2012
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