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Antimicrobial compounds from seaweedsassociated bacteria and fungi

Ravindra Pal Singh, Puja Kumari &


C.R.K.Reddy

Applied Microbiology and


Biotechnology
ISSN 0175-7598
Volume 99
Number 4
Appl Microbiol Biotechnol (2015)
99:1571-1586
DOI 10.1007/s00253-014-6334-y

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Appl Microbiol Biotechnol (2015) 99:15711586
DOI 10.1007/s00253-014-6334-y

MINI-REVIEW

Antimicrobial compounds from seaweeds-associated bacteria


and fungi
Ravindra Pal Singh & Puja Kumari & C. R. K. Reddy

Received: 27 August 2014 / Revised: 14 December 2014 / Accepted: 15 December 2014 / Published online: 31 December 2014
# Springer-Verlag Berlin Heidelberg 2014

Abstract In recent decade, seaweeds-associated microbial communities have been significantly evaluated for functional and
chemical analyses. Such analyses let to conclude that
seaweeds-associated microbial communities are highly diverse
and rich sources of bioactive compounds of exceptional molecular structure. Extracting bioactive compounds from seaweedassociated microbial communities have been recently increased
due to their broad-spectrum antimicrobial activities including
antibacterial, antifungal, antiviral, anti-settlement, antiprotozoan,
antiparasitic, and antitumor. These allelochemicals not only provide protection to host from other surrounding pelagic microorganisms, but also ensure their association with the host.
Antimicrobial compounds from marine sources are promising
and priority targets of biotechnological and pharmaceutical applications. This review describes the bioactive metabolites reported from seaweed-associated bacterial and fungal communities
and illustrates their bioactivities. Biotechnological application
of metagenomic approach for identifying novel bioactive metabolites is also dealt, in view of their future development as a strong
R. P. Singh (*) : P. Kumari : C. R. K. Reddy (*)
Discipline of Marine Biotechnology and Ecology, CSIRCentral
Salt and Marine Chemicals Research Institute,
Bhavnagar 364002, Gujarat, India
e-mail: ravindrapal.1441@gmail.com
e-mail: crk@csmcri.org
R. P. Singh
Laboratory of Microbial Technology, Department of Bioscience and
Biotechnology, Faculty of Agriculture, Kyushu University,
Fukuoka 812-8581, Japan
P. Kumari
Institute of Plant Sciences, Agricultural Research Organization
(ARO), Volcani Center, PO Box 6, Bet Dagan 50250, Israel
C. R. K. Reddy
Academy of Scientific and Innovative Research (AcSIR),
New Delhi, India

tool to discover novel drug targets from seaweed-associated microbial communities.


Keywords Biotechnological application . Seaweed .
Antibacterial . Antifungal . Antifouling . Bioactive
compounds . Metagenomics

Introduction
Marine waters comprise a high diversity of microbial life, predominantly including bacteria, fungi, viruses, spores, and actinomycetes (Engel et al. 2002; Harder 2009). These organisms also
settle on marine animals and plants, besides occurring in sea
surface, and form unique associations with their hosts (Lafi
et al. 2005; Webster et al. 2008; Singh and Reddy 2014).
Associated microorganisms utilize nutrients (e.g., carbon) source
produced by their host and in return protect them from harmful
entities in surrounding by secretion of certain biological active
molecules called bioactives (Armstrong et al. 2001; Jiang et al.
2001; Jamal et al. 2006; Lane and Kubanek 2008). Seaweeds are
part of highly productive ecosystems and are habitats of numerous bioactive compounds producing microorganisms. Bioactive
compounds obtained from associated microorganisms are known
for broad range of biological effects such as antimicrobial,
antisettlement, antiprotozoan, antiparasitic, and antitumors
(Egan et al. 2001, 2008; Penesyan et al. 2011; Lee et al. 2013).
For example, Egan et al. (2001; 2002) identified a number of
Pseudoalteromonas strains from surface of Ulva australis that
exhibited antisettlement activity against invertebrate larvae and
algal spores as well as antibacterial and antifungal activities.
Mostly, bioactive compounds producing microorganisms are
evolved through high competitive environment due to nutrient
and space limitation on their host surface that led them to produce

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allelochemicals capable of preventing secondary colonisation


(Egan et al. 2001, 2008). These bioactives are secondary metabolites and have exceptional molecular structure as compared to
those produced by terrestrial microorganisms (Fenical and
Jensen 1991; Fenical 1993; Clardy et al. 2006; Penesyan et al.
2009, 2010). The bioactivities of such secondary metabolites
indicate that they possess pharmaceuticals, industrial, agricultural, and biotechnological applications (Armstrong et al. 2001;
Penesyan et al. 2011).
Recently, seaweed-associated microorganisms have significantly been investigated for analysis of microbial communities
and identification of their bioactivities (Molinski et al. 2009;
Penesyan et al. 2009, 2011, 2013a, b; Burke et al. 2011;
Bondoso et al. 2013; Goecke et al. 2013; Hollants et al. 2013;
Tebben et al. 2014). Nevertheless, most of the studies have been
carried out to understand bioactivities produced mostly from
bacterial and fungal sources associated with seaweeds as compared to other microorganisms, which remains mostly unexplored (Egan et al. 2008). Therefore, this review discusses the
significance of associated bacteria and fungi for targeting isolation of bioactive molecules and exploring metagenomic approach for searching broad range bioactives (Fig. 1).

Bioactivities of seaweeds-associated bacteria


Among other microbial communities living on the seaweed
surface, bacteria are ubiquitous and present as either extracellular or in the cytosol of living host cells and determine the
different stages of life span of Ulva and Gracilaria species
(Holmstrm et al. 2002; Tait et al. 2009; Burke et al. 2011;
Singh et al. 2011a, b). Several studies have been demonstrated
that seaweed-associated bacteria play crucial roles in

Appl Microbiol Biotechnol (2015) 99:15711586

determining the normal morphology, growth, and development


of the host (Nakanishi et al. 1999; Matsuo et al. 2003; Marshall
et al. 2006; Singh and Reddy 2014). For instance, Matsuo et al.
(2005) found a thallusin bioactive molecule, which was responsible for morphogenesis in Monostroma oxyspermum.
As above mentioned, seaweeds can also be considered as rich
sources for microbial nutrients that ultimately leads to high competition between different microbial communities (Burgess et al.
1999; Armstrong et al. 2001; Penesyan et al. 2009). Such circumstances force bacteria to evolve in such a way that they can
produce certain antimicrobial compounds to sustain competition
from other microbes. This selection further revealed that associated bacterial communities might produce novel drugs as compared to other surface dwelling microbes to ensure their position
on host. Thus, it has been found that these associated bacteria
produce various bioactive compounds including haliangicin,
violacein, pelagiomicin A, korormicin, macrolactines, and chlorophyll d which exhibit the antifungal, antiprotozoal,
antisettlement, antibiotic activity against gram-negative bacteria,
gram-positive, and photosynthetic activity, respectively
(Imamura et al. 1997; Yoshikawa et al. 1997, 1999; Gerard
et al. 1997; Fudou et al. 2001; Murakami et al. 2004; Matz
et al. 2008; Goecke et al. 2010). Bioactive compounds extracted
from seaweed-associated microorganisms have dramatically increased in past decades with nearly 600 % from the last century
(Gulder and Moore 2009; Waters et al. 2010). Such increasing
evidences are proved that marine-associated bacteria produce
novel valuable compounds having the higher chances for development of pharmaceutical drugs (Debnath et al. 2007; IsmailBen Ali et al. 2012; Tebben et al. 2014). For instance, Lemos
et al. (1985) demonstrated that 17 % of 224 isolates displayed
antibacterial activity affiliated with five species of green and
brown algae. Kanagasabhapathy et al. (2006) reported that

Fig. 1 Graphical represent of green seaweed, existing of bacterial and fungal communities on their surface and structure of bioactive compounds

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20 % of epiphytic bacterial strains associated with nine species of


brown alga exhibit antibiotic activities. Similarly, Penesyan et al.
(2009) isolated 325 bacterial isolates from Delisea pulchra and
U. australis and 12 % of them showed antibacterial activities.
Moreover, high proportions of antimicrobial producing bacterial
isolates have also been reported. Kanagasabhapathy et al. (2008)
reported that 33 % of epiphytic bacterial strains associated with
nine species of red alga exhibit antibiotic activities. Burgess et al.
(1999) found 35 % of the surface-associated bacteria having
antibacterial activities. Wiese et al. (2009) studied the antibiotic
active bacteria associated with brown algae Saccharina latissima
and found that 50 % associated bacterial strains inhibited the
growth of either gram-negative or gram-positive bacteria or
yeast. Ma et al. (2009) isolated 192 bacterial strains and out of
them 63 strains (32.81 %) revealed antisettlement effect against
Ulva lactuca as well as anti-larval activity. JanakiDevi et al.
(2013) isolated 126 bacteria from five different seaweeds
(Gracillaria corticata, Geledium pussilum, Hypnea musiformis,
Padina gymnosphora, and Valoniopsis pachynema) which
showed antibacterial activity (2.6 to 16 mm inhibitory zone)
against Escherichia coli, Staphylococcus sp., Klebshilla
pneumonia, Pseudomonas aeroginosa, Micrococcus sp.,
Salmonells sp., Vibrio cholera, Shigella dysenteriae, and
Serratia sp.
Recent studies revealed that bacterial communities associated
with seaweeds are significantly different from marine waters
(Burke et al. 2011; Tujula et al. 2010; Lachnit et al. 2011). The
seaweed surface is predominately occupied by diverse groups of
bacterial communities belonging to Alphaproteobacteria,
Gammaproteobacteria, Firmicutes, Actinobacteria,
Bacteroidetes, and Planctomycetes (Burke et al. 2011; Tujula
et al. 2010; Longford et al. 2007; Bondoso et al. 2013;
Hollants et al. 2013). Therefore, antimicrobial compounds extracted from associated bacterial communities are belonged to
various genera such as Pseudomonas, Pseudoalteromonas,
Stenotrophomonas, Vibrio, Alteromonas, Shewanella,
Streptomyces, and Bacillus species (Wiese et al. 2009). Burgess
et al. (2003) identified most of the Bacillus strains associated with
antifouling activities. Epiphytic Vibrio species present on green
alga Ulva reticulata significantly inhibited settlement and metamorphosis of polychaete larvae and may attribute to the host alga
protection against further fouling (Dobretsov and Qian 2002).
Similarly, epiphytic Pseudoalteromonas tunicata and
Roseobacter gallaeciensis are found in association with green
alga U. australis and produce a range of extracellular inhibitory
compounds against marine fungi, bacteria, invertebrate larvae,
and algal spores (Holmstrm et al. 2002; Rao et al. 2007). In
contrast, three epiphytic strains of Pseudoalteromonas sp. isolated from seaweeds exhibited autoinhibitory activities (Holmstrm
et al. 2002). Autoinhibitory activity might serve to prevent the
predominance of any single specific bacterial species and assist
in maintaining the bacterial diversity on the specific host. Some
gram-positive and gram-negative bacteria produce autolysin

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compounds, which hydrolyse the peptidoglycan of the bacterial


cell wall and lead to the release of intracellular substances (Li
et al. 1998). Kumar et al. (2011) isolated ten residential bacteria
from tropical green alga U. lactuca and found that most of the
epiphytic isolates showed antibacterial and antidiatom activity
against other resident bacteria and a diatom, Cylindrotheca
fusiformis, respectively. Furthermore, their results indicated that
Pseudoalteromonas genus has a broad-spectrum activity whereas
Bacillus, Vibrio, and Shewanella mostly revealed antidiatom activity. The antibacterial compounds produced by seaweedassociated Alteromonas aurantia (Gauthier and Breittmayer
1979), Alteromonas rubra (Gauthier 1979), and Alteromonas
luteoviolacea (Gauthier 1976) were composed of high molecular
mass molecules, suggested to inhibit bacterial respiration and
reduce further fouling. Therefore, Silva-Aciares and Riquelme
(2008) studied the effect of biofilms and extracellular products
(EP) of the indigenous bacterium Alteromonas sp. strain Ni1LEM (associated with red macroalga, Rhodymenia sp.) on zoospores germination and settlement of green alga U. lactuca. They
also found a high molecular weight protein, 3500 Da that was
thermostable, hydrophilic in nature with high antifouling
potential.
The present study is hereby summarizing the bioactivities
of seaweed-associated bacterial genera which are highly
promising candidates for pharmaceutical applications.
Pseudoalteromonas
Those species of genus Pseudoalteromonas that are present in
association with marine macroalgae produce extracellular compounds that inhibits or control fouling of other species on the
host surface (Holmstrom and Kjelleberg 1999). These activities
related to the production of some microbial compounds. For
example, two important diketopiperazines, cyclo-(L-prolyl-Lglycine) and cyclo-(L-phenylalanyl-4R-hydroxy-L-proline),
and 2,4-dibromo-6-chlorophenol were extracted from Padina
australis associated with marine bacteria Pseudoalteromonas
luteoviolacea (Jiang et al. 2001). Both diketopiperazines stimulated antibiotic production in this strain whereas 2,4-dibromo6-chlorophenol showed antibacterial activity against cystic fibrosis associated with pathogen Burkholderia cepacia and
methicillin resistant Staphylococcus aureus (MRSA).
The novel korormicin drug (Fig. 2a) originally was obtained from Halimeda sp. associated with bacterium,
Pseudoalteromonas sp. F-420 and was significantly investigated for its biological activity against gram-negative bacteria
(Yoshikawa et al. 1997). Further study of Yoshikawa et al.
(2003) identified five derivatives of original compound
korormicin from Pseudoalteromonas sp. F-420 which showed
antibacterial activity against marine Vibrio spp., Salinivibrio
costicola and Pseudoalteromonas haloplanktis, but no activity
against terrestrial bacterium. Interestingly, the respiratory
chain of marine bacterium Vibrio alginolyticus and halophilic

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Fig. 2 Some representatives of


structurally potential bioactive
compounds obtained from
seaweed associated bacteria. a
Base structure of korormicin; b
tetrodotoxin, c 2,4diacetylphloroglucinol, d
haliangicin, and e tropodithietic
acid

Vibrio costicolus has a unique Na+ -dependent NADHquinone reductase that functions as a primary Na+ pump and
is required for its maximum activity (Unemoto et al. 1977;
Hayashi et al. 2002). The Na+-translocating NADH-quinone
reductase (NQR) of V. alginolyticus is composed of six structural genes, namely nqrA, nqrB, nqrC, nqrD, nqrE, and nqrF
(Beattie et al. 1994; Hayashi et al. 1994; 1995). It has been
found that korormicin specifically inhibited the NQR complex
of these marine halophilic Vibrio species (Nakayama et al.
1999). Later, homology search of the nqr operon revealed that
the Na+-pumping NQR complex is widely distributed among
gram-negative pathogenic bacteria (Hayashi et al. 2002). This
drug is potentially suggested for pharmaceutical application.
Recently, Tebben et al. (2014) identified 13 natural products from Pseudoalteromonas strain J010, which were isolated from surface of the crustose coralline alga Neogoniolithon
fosliei. Among them, a new bromopyrrole, 4-((3,4,5-tribromo1H-pyrrol-2-yl) methyl)phenol and five new korormicins G
K were obtained which exhibited antibacterial activity.
Interestingly, this strain also produced a coral larval metamorphosis inducer compound, tetrabromopyrrole which had a
broad-spectrum activity against the tested bacteria, fungi,
and protozoan (Tebben et al. 2011, 2014).
Two more novel compounds (violacein and YP1) were
obtained from U. australis associated with P. tunicata
(Franks et al. 2006; Matz et al. 2008). Violacein (an alkaloid)
producing P. tunicata and P. ulvae showed antiprotozoal activity against amoeba Acanthamoeba castellanii at nanomolar
concentration (Matz et al. 2008). It also demonstrated that
violacein induces apoptosis-like cell death program in protozoan predators. It has been observed that violacein produced
by Chromobacterium violaceum induces apoptosis in mammalian cell lines (Ferreira et al. 2004; Kodach et al. 2006).
Therefore, it could be a novel therapeutic agent to treat cancerous cells (Matz et al. 2008). Recently, Subramaniam et al.

(2014) demonstrated that synergistic administration of


violacein with available antibiotics such as azithromycin, gentamicin, kanamycin, and cefadroxil could increase its potential. It was observed that violacein-azithromycin and
violacein-kanamycin combination exhibited significant fractional inhibitory concentration indices (0.3) against
Salmonella typhi as compared to violacein alone (5.7 g/
mL). Similarly, violacein-gentamicin and violaceincefadroxil combination had MIC of 1.0 g/mL against
S. aureus as compared to violacein alone (5.7 g/mL).
P. tunicata produces YP1 (a tambjamine class of compound),
a yellow pigment compound that contains a 2,2-bipyrrolering
with an unsaturated 12 carbon alkyl chain (Franks et al. 2005)
and is reported for its antifungal activity (Franks et al. 2006).
Pseudomonas
The genus Pseudomonas species are also known to produce
several antimicrobial compounds by which they protect host
alga from harmful microorganisms. An important drug tetrodotoxin (TTX, a potent neurotoxin, Fig. 2b) initially isolated
from toxic pufferfish (Yokoo 1950) was also obtained from
Pseudomonas sp. associated with Jania sp. (Yasumoto et al.
1986), and the structure was elucidated in 1964 (Tsuda et al.
1964; Woodward 1964; Goto et al. 1965). TTX inhibits nerve
and muscle conduction via binding to the voltage-gated Na+
channels in nerve cell membranes and thereby preventing action potential generation and propagation (Lee and Ruben
2008), ultimately leading to death of the organism.
Magnesidin, a novel magnesium-containing antibiotic, was
obtained from novel bacterium Pseudomonas magnesiorubra
associated with Caulerpa peltata (Gandhi et al. 1973). It is a
complex structure of the magnesium salts of two tetramic
acids, l-acetyl-3-n-hexanoyl-5-ethylidene tetramic acid (n=
4) and l-acetyl-3-n-octanoyl-5-ethylidene tetramic acid (n=

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6). It has a strong antibacterial activity against Staphylococcus


and Bacillus spp. (Gandhi et al. 1973). Another compound 2,
4-diacetylphloroglucinol, DAPG (Fig. 2c) was obtained from
novel bacterium Pseudomonas sp. strain AMSA. This strain
was originally isolated from a red alga Ceratodyction
spongiosum (Isnansetyo et al. 2001) and strongly inhibited
growth of the Methicillin-resistant S. aureus (MRSA).
Further study of Kamei and Isnansetyo (2003) found that
DAPG inhibited growth of MRSA at 1 mg/L and
V. parahaemolyticus at 24 mg/L. It was also observed that
DAPG stables at temperature ranging from 35 to 70 C and
pH at 2 to 7.
Four important compounds massetolides A, B, C, and D
were extracted from EtOAc-fraction of the Pseudomonas sp.
associated with an unidentified red alga (Gerard et al. 1997).
These novel cyclic depsipeptides inhibited growth of
Mycobacterium tuberculosis and M. avium-intracellulare
(Gerard et al. 1997). In another study, two new peptides
cyclo-[phenylalanyl-prolyl-leucylprolyl] and
cyclo-[isoleucyl-prolyl-leucyl-alanyl] were obtained from a
Pseudomonas sp. associated with Japanese seaweed Diginea
sp. (Rungprom et al. 2008). These peptides were found to
inhibit growth of S. aureus, Micrococcus luteus, Bacillus
subtilis, E. coli, and Vibrio anguillarum. Massetolide A obtained from Pseudomonas fluorescens was found as a biological agent to control the growth of late blight producing fungal
pathogens Phytophthora infestans (Tran et al. 2007).
Recently, Ravisankar et al. (2013) identified an alkaloid
from Pseudomonas sp. associated with Padina
tetrastromatica. This compound inhibited growth of human
pathogenic bacteria, K. pneumoniae and Pseudomonas
aeruginosa with 15 and 10 mm inhibitory zone, respectively,
at a concentration of 300 g.
Bacillus
Among firmicutes group, Bacillus species are dominantly present on the surface of diverse seaweeds (Lachnit et al. 2009;
Tujula et al. 2010; Burke et al. 2011; Lachnit et al. 2011).
These species have been reported for antibacterial and antifungal activities (Burgess et al. 2003; Kanagasabhapathy et al.
2006; Penesyan et al. 2010). An important antibacterial protein
(30.7 kDa) was obtained from Bacillus licheniformis associated
with Fucus serratus. This novel protein showed activity against
MRSA, vancomycin-resistant enterococci, and Listeria
monocytogenes (Jamal et al. 2006). A series of novel
macrolactin G, H, I, J, K, L, and M was extracted from
Bacillus sp. PP19-H3 associated with seaweed, Schizymenia
dubyi (Nagao et al. 2001). It was also found to produce
macrolactines A and F that were previously extracted from
Actinomadura sp. (Kim et al. 1997) and Bacillus sp.
(Jaruchoktaweechai et al. 2000), respectively. Among all
macrolactines, macrolactin A had strong antibacterial activity

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against S. aureus IFO 12732 and B. subtilis IFO 3134 (Nagao


et al. 2001), while none of them inhibited growth of the E. coli
IFO 3301 and S. costicola (ATCC33508). However, recently
reported novel macrolactin S (obtained from a marine Bacillus
sp.) and macrolactin W (obtained from a marine Bacillus sp.
09ID194) exhibited broad-spectrum antibacterial activity
against gram-positive and gram-negative pathogenic bacteria
(Lu et al. 2008; Mondol et al. 2011). Additionally, a novel
polyketide family member 7-O-methyl-5-hydroxy-3heptenoate-macrolactin was also obtained from seaweed,
Anthophycus longifolius associated with B. subtilis MTCC
10403 strain (Chakraborty et al. 2014). The particular compound showed 1222 mm inhibitory zone against different species of Vibrio sp.
Interestingly, a bacteriocin (lichenicidin, a class of
lentibiotics) was also confirmed from seaweeds-associated
B. licheniformias and also suggested that seaweed-associated
Bacillus spp. could be source for novel bacteriocin (Prieto
et al. 2012). Subsequently, another bacteriocin (approximately
8 kDa molecular weight) was partially characterized from
seaweed-associated Staphylococcus haemolyticus MSM and
exhibited strong antibacterial activity against human pathogenic bacteria (Suresh et al. 2014).

Bioactivities of some other seaweed-associated bacterial


groups
Some other bacterial groups also produce potential bioactive
drugs. For instance, a halophilic gram-negative bacterium
Pelagiobacter variabilis isolated from a brown alga
Pocockiella variegata (Imamura et al. 1997) produce an important drug pelagiomicin A, a phenazine antibiotic. This
compound exhibits activity against gram-positive and gramnegative bacteria and has antitumor activity against HeLa
(IC50 0.04 g/mL), BALB3T3 (IC50 0.02 g/mL), and
BALB3T3/H-ras (IC50 0.07 g/mL) in vivo.
An antifungal drug, haliangicin (Fig. 2d), was obtained
from marine seaweed (undefined) associated with bacterium,
Haliangium luteum (Fudou et al. 2001). It has potent activity
against filamentous fungi comparable to antifungal known
drugs amphotericin B and nystatin and other drugs belonging
to -methoxyacrylate type compounds (Fudou et al. 2001). It
is suggested that haliangicin blocked the electron flow within
cytochrome b-cl part of the electron transport chain of mitochondria. Haliangicin was also reported to possess cytotoxicity against mouse P388 cell lines (IC50 0.21 M) (Fudou et al.
2001).
An epiphytic bacterium, Pseudovibrio sp. D323 isolated
from D. pulchra produced antibacterial compound
tropodithietic acid (TDA) (Fig. 2e). TDA has a broadspectrum effect against large range of bacteria belonging to

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Proteobacteria, Actinobacteria, Firm icutes , and


Bacteroidetes (Penesyan et al. 2011). Interestingly, it was
found that only TDA producing bacterial strains are resistant
to this compound while non-TDA producing strains were sensitive (Bruhn et al. 2007; Penesyan et al. 2011). Although, it is
suggested that TDA producing bacterial strains may possess
resistance mechanism to prevent auto-inhibition but this
mechanism is still not well defined.
Latest, Braa et al. (2014) identified several bioactive compounds from seaweed-associated (also found with coral)
Streptomyces strains, Streptomyces cyaneofuscatus M-27
and Staphylococcus carnosus M-40. These compounds are
daunomycin (anticancer), cosmomycin B (antitumor),
galtamycin B (antitumor), maltophilins (antifungal), and
lobophorins (anti-inflammatory, anti-BCG and antituberculosis) and are known to display several biological activities.
Recently, Suvega and Kumar (2014) isolated 673 isolates
from different seaweeds, sediments, and soil. Maximum bacterial isolates were obtained from different seaweeds and
40.2 % isolates belonged to the species of Bacillus sp.
Interestingly, maximum bioactive compounds producing bacterial isolates (epibiotics, 39.54 % and endobiotics, 40.74 %)
were obtained from the surface of seaweeds as compared to
the seawater (8.61 %) and the sediments (11.11 %). These
isolates produced antimicrobial compounds and were active
against plant pathogens (Xanthomonas axonopodis pv. citri,
X. oryzaepv. oryzae and Ustilaginoidea virens). Proteins present in the extracellular components of these bacterial isolates
were highly active at pH 7.0 and showed antibacterial activity
up to 40 C and antifungal property up to 60 C. Whereas nonpolar lipophilic compounds extracted from these active bacteria only displayed antifungal activity (Suvega and Kumar
2014).
Kanagasabhapathy et al. (2009) screened 96 bacterial isolates obtained from a brown alga Colpomenia sinuosa for
identification of quorum quenching against Serratia rubidaea
JCM 14263, as an indicator organism which controls the production of red pigment, prodigiosin, and is mediated by acylhomoserine lactone (quorum sensing molecule). Out of them,
only 12 % of the isolates inhibited the production of
prodigiosin. The phylogenetic analysis revealed that those
isolates belonged to Bacillaceae, Pseudomonadaceae, and
Pseudoalteromonadaceae. Cho and Kim (2012) isolated one
actinomyces (Streptomyces cinnabarinus) and bacteria
(Alteromonas sp.) from rhizospheric part of the seaweed and
observed that in presence of Alteromonas sp., S. cinnabarinus
increased production of lobocompactol which showed significant antifouling activity against Ulva pertusa and the diatom
Navicula annexa with 0.18 and 0.43 g/mL, respectively. It
also showed antifouling activity against bacteria. VillarrealGmez et al. (2010) isolated 35 bacterial strains from different
seaweeds and among them Cc51 (associated with Centroceras
clavulatum), Sm36 (associated with Sargassum muticum), and

Appl Microbiol Biotechnol (2015) 99:15711586

Eb46 strains (associated with Endarachne binghamiae)


showed anticancer activity, with IC50 values of 6.492, 5.531,
and 2.843 g/mL, respectively.

Bioactivities of seaweeds-associated fungi


Seaweeds represent second largest, source of diverse assemblage of marine fungi (Bugni and Ireland 2004; Schulz et al.
2008; Loque et al. 2010; Suryanarayanan et al. 2010; Godinho
et al. 2013). Seaweed-associated fungi mostly include parasites, saprobes, or asymptomatic fungal endosymbionts
(Bugni and Ireland 2004; Zuccaro et al. 2008; Loque et al.
2010; Suryanarayanan et al. 2010). A number of seaweeds
encompassing genera of Adenocystis, Ascophyllum,
Desmarestia, Dictyota, Fucus, Lobophora, Padina,
Phaeurus, Sargassum, Stocheospermum, and Turbinaria (belonging to Phaeophyceae), Gelidiella, Gracilaria,
Grateloupia, Halymenia, Palmaria, Plocamium, Portieria,
Pyropia (belonging to Rhodophyceae) and Acrosiphonia,
Caulerpa, Halimeda, Monostroma, and Ulva (belonging to
Chlorophyceae) have been extensively studied worldwide
for their fungal associations (Table 1). Most of the studies
revealed that ascomycetes and anarmorphic fungi were the
dominant fungal endosymbionts (Schulz et al. 2008;
Zuccaro et al. 2008; Loque et al. 2010; Suryanarayanan
et al. 2010; Suryanarayanan 2012; Suryanarayanan et al.
2012; Flewelling et al. 2013; Godinho et al. 2013; Furbino
et al. 2014). Red and brown seaweeds harbored greater fungal
species diversity as compared to green seaweeds
(Suryanarayanan et al. 2010). It has been proposed that short
life cycle of some of the green seaweeds and characteristically
slow growth of the endosymbionts could together be responsible for low fungal diversity in green seaweeds (Zuccaro and
Mitchell 2005). Members of genera Acremonium, Alternaria,
Arthrinium, Aspergillus, Cladosporium, Fusarium,
Geomyces, Penicillium, and Phoma (Zuccaro et al. 2003;
2008; Loque et al. 2010; Suryanarayanan et al. 2010;
Flewelling et al. 2013; Godinho et al. 2013; Furbino et al.
2014) were the most common fungal endosymbionts in different seaweeds (Table 1).
Like bacteria, seaweed-associated fungi also produce numerous novel bioactive metabolites that exhibit anticancer,
antibacterial, antiplasmodial, anti-inflammatory, nematicidal,
antiviral, and antiangiogenic activities (Suryanarayanan et al.
2010; Oliveira et al. 2012; Flewelling et al. 2013; Godinho
et al. 2013; Lee et al. 2013; Furbino et al. 2014; Suja et al.
2014). Suryanarayanan and coworkers (Suryanarayanan et al.
2010; Suryanarayanan 2012) demonstrated that fungal isolates from green, red, and brown seaweeds produce antialgal,
antifungal, and insecticidal metabolites which may help in
deterring colonization of algal thalli by other microbes thereby
reducing competition and in warding off herbivores.

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Table 1

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List of fungi isolated from seaweeds

Seaweed host

Seaweed-associated fungi

Acrosiphonia arcta

Geomyces sp., Metschnikowia australis, Penicillium sp., Candida sake, Cladosporium sp., Godinho et al. 2013
Cladosporium tenuissimum, Debaryomyces hansenii, Mortierella sp., Phoma sp.,
Thelebolus globosus
Aspergillus spp., Aureobasidium pullulans, Chaetomium spp., Cladosporium spp., Fusarium Suryanarayanan et al. 2010
spp., Mucor sp., Penicillium spp., Phoma sp., Pyrenochaeta sp.
Aspergillus spp., Chaetomium spp., Curvularia spp., Paecilomyces spp., Penicillium spp.
Suryanarayanan et al. 2010

Caulerpa racemosa

Caulerpa
scalpelliformis
Caulerpa
Aspergillus spp., Chaetomium spp., Cladosporium spp., Fusarium spp., Myrothecium sp.,
sertularioides
Penicillium spp., Phialophora sp.
1
1
Desmarestia
[Metschnikowia australis, Penicillium sp.], 2[Geomyces pannorum
menziesii,
2
D. anceps
Halimeda macroloba Aspergillus spp., Chaetomium spp., Paecilomyces spp., Penicillium spp., Trichoderma sp.
Monostroma hariotii

Ulva lactuca

Ulva fasciata
Ulva intestinalis

References

Suryanarayanan et al. 2010


1

Godinho et al. 2013, 2Loque


et al. 2010

Suryanarayanan et al. 2010

[Geomyces destructans, Penicillium sp., Meyerozyma guilliermondii, Cryptococcus cf.


Godinho et al. 2013, 2Furbino
laurentii, Cordycipitaceae sp., Helotiales sp., Hyaloscyphaceae sp., Rhodotorula
et al. 2014
mucilaginosa], 2[Penicillium steckii, Penicillium sp., Aspergillus sp., Aspergillus
tabacinus, Cladosporium sp., Penicillium citrinum, Penicillium crustosum Thom,
Penicillium crustosum, Metschnikowia australis, Guehomyces pullulans, Cryptococcus
albidosimilis, Cryptococcus adeliensis, Rhodotorula larynges, Rhodotorulaminuta,
Rhodotorula mucilaginosa, Phoma sp., Pseudogymnoascus sp., Cystofilobasidium
firmominiatum, Meyerozyma guilliermondii]
1
[Aspergillus spp., Chaetomium spp., Cladosporium spp., Nigrospora sp., Penicillium spp.], 1Suryanarayanan et al. 2010,
2
2
[Leotiomyceta sp., Eurotium sp., Stilbella fimetaria, Penicillium sp., Pseudeurotium
Flewelling et al. 2013,
bakeri]
Aspergillus spp., Chaetomium spp., Curvularia spp., Paecilomyces spp.
Suryanarayanan et al. 2010
1

Gelidiella acerosa

[Penicillium sp., Penicillium discolor, Antarctomyce spsychrotrophicus, Cryptococcus


victoriae, Engyodontium sp., Geomycesluteus, Helotiales sp., Mycoarthris cf. corallines,
Penicillium sp., Thelebolus globosus], 2[Bionectria ochroleuca, Leptosphaeria sp.,
Penicillium sp., Cordyceps sp.]
Alternaria spp., Aspergillus sp., Penicillium spp., Phoma sp.

Gracilaria spp.

Aphanocladium sp., Aspergillus sp., Monilia sp., Paecilomyces spp.

Suryanarayanan et al. 2010

Grateloupia
lithophila
Halymenia spp.

Aspergillus sp., Cladosporium spp.

Suryanarayanan et al. 2010

Aspergillus sp., Cladosporium spp., Drechslera spp., Emericella nidulans, Paecilomyces spp.,
Penicillium spp., Phoma sp.
Palmaria decipiens 1[Penicillium sp., Geomyces sp., Acremonium sp., Fusarium sp., Yamadazyma mexicana,
Aspergillus sp., Chaetomium sp., Penicillium spinulosum] 2[Cryptococcus carnescens]
Seaweed host
Seaweed associated Fungi
Portieria hornemanii Aspergillus sp., Cladosporium spp., Memnoniella sp., Penicillium spp., Phomopsis sp.,
Trimmatostroma sp.
Pyropia endiviifolia Cladophora maronum, Penicillium spp., Pseudogymnoascus spp., T. globosus, Aspergillus
sp., Aspergillus protuberus, Antarctomyces psychrotrophicus, Cladosporium lignicola,
Mortierella antarctica, Oidiodendron truncatum, Metschnikowia australis, Dipodascus
australiensis, Meyerozyma guilliermondii, Verticillum sp., Lecanicillium sp.
1
Adenocystis spp.
[Penicillium spp., Aspergillus conicus, Geomyces sp., Debaryomyces hansenii, Meyerozyma
caribbica] 2[Antarctomyces psychrotrophicus, Geomyces pannorum, Oidiodendron sp.,
Penicillium sp., Phaeosphaeria herpotrichoides, Algicolous fungi]
Ascophyllum
Aspergillus fumigatus, Lichtheimia corymbifera, Cladosporium sp., Dendryphiella salina
nodosum
Dictyota dichotoma Aspergillus spp., Trichoderma sp.

Suryanarayanan et al. 2010

Suryanarayanan et al. 2010


Godinho et al. 2013
References
Suryanarayanan et al. 2010
Furbino et al. 2014

Godinho et al. 2013, 2Loque


et al. 2010

Flewelling et al. 2013


Suryanarayanan et al. 2010

Fucus vesiculosus

[Lindra, Lulworthia, Engyodontium, Sigmoidea/ Corollospora complex, and Emericellopsis/ Zuccaro et al. 2008, 2Flewelling
Acremonium-like ribotypes], 2[Aspergillus fumigatus, Coniothyrium sp., Penicillium sp.,
et al. 2013
Coniothyrium sp.]
Aspergillus fumigatus, Coniothyrium sp., Penicillium sp., Alternaria sp.
Flewelling et al. 2013

Fucus spiralis

Penicillium sp.

Fucus serratus

Godinho et al. 2013,


2
Flewelling et al. 2013

Flewelling et al. 2013

Lobophora variegata Aspergillus spp., Chaetomium spp., Emericella nidulans, Nigrospora sp.

Suryanarayanan et al. 2010

Padina
tetrastomatica

Suryanarayanan et al. 2010

Acremoniella sp., Aspergillus spp., Chaetomium spp., Monodictys sp., Paecilomyces spp.,
Penicillium spp.

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Appl Microbiol Biotechnol (2015) 99:15711586

Table 1 (continued)
Seaweed host

Seaweed-associated fungi

References

Padina gymnospora

Aspergillus spp., Chaetomium spp., Cladosporium spp., Phoma sp., Trichoderma sp.

Suryanarayanan et al. 2010

Phaeurus antarcticus Penicillium sp., Geomyces sp., Aspergillusterreus, Eurotium herbariorum, Eurotium repens, Godinho et al. 2013
Penicillium steckii
Plocamium
Metschnikowia sp., Acremonium sp., Cladosporium sp., Penicillium biourgeianum
Flewelling et al. 2013
cartilagineum
1
Sargassum sp.
[Corollospora sp.], 2[Alternaria spp., Aspergillus spp., Colletotrichum sp., Drechslera spp., 1Schulz et al. 2008,
2
Suryanarayanan et al. 2010
Helicosporium sp., Nigrospora sp., Taeniolella sp., Varicosporium sp.]
Sargassum wightii
Stocheospermum
marginatum
Turbinaria spp.

Aspergillus spp., Cladosporium spp., Emericella nidulans, Nigrospora sp., Oidiodendron sp., Suryanarayanan et al. 2010
Paecilomyces spp.
Alternaria spp., Aspergillus spp., Chaetomium spp., Emericella nidulans, Nigrospora sp.
Suryanarayanan et al. 2010
Aspergillus spp., Chaetomium spp., Cladosporium spp., Colletotrichum sp., Curvularia spp., Suryanarayanan et al. 2010
Drechslera spp., Emericella nidulans, Fusarium spp., Monodictys sp., Nigrospora sp.,
Paecilomyces spp., Phaeotrichoconis sp., Phialophora sp., Phoma sp.

Superscript numbers represent their respective references

Additionally, it has been found that endophytes produce antioxidant chemicals that protect their host plants from diseases,
drought, and heavy metal toxicity by increasing tolerance of
the host to oxidative stress (White and Torres 2010).
Flewelling et al. (2013) demonstrated that the mycelial and
broth extracts from endophytic fungal isolates isolated from
different seaweeds showed potent bioactivities wherein, 15
extracts had antimicrobial activities with >80 % inhibition
against S. aureus, P. aeruginosa, and Candida albicans.
Also, seven extracts obtained from Microdochium sp. (isolated from Porphyra sp.), Sterile Pigmented II and III (isolated
from Ulva intestinalis), Penicillium sp. V and VI (isolated
from Fucus spiralis) had larvicidal activities with a LC50 <
100 g/mL. Mathan et al. (2013) screened 19 seaweed endophytic fungal strains for their bioactivity against human and
fish pathogenic bacteria such as E. coli, S. aureus,
V. parahaemolyticus, Klebsiella oxycota, V. cholera, and fish
bacterial pathogens, Aeromonas hydrophila, Enterobacter
aerogens, Flavobacterium sp., Micrococcus sp., and
P. fluorescens of which six strains showed >10 mm of zone
of inhibition. These authors proposed that antibacterial
activity might be due to the presence of bioactive
metabolites produced by the seaweed endophytic fungi.
Recently, Furbino et al. (2014) collected 239 fungal isolates
from 390 thalli of the endemic Antarctic macroalgae,
Monostroma hariotii and Pyropia endiviifolia, and found that
extracts of these endemic and cold-adapted fungi displayed
biological activities. Only six fungal taxa potentially showed
antifungal activity with 6196 % of inhibition. The extracts of
Pseudogymnoascus sp., Guehomyces pullulans, and
Metschnikowia australis showed selective antifungal activities against C. albicans, Candida krusei, and Cladosporium
sphaerospermum. The extract of Dipodascus australiensis
inhibited selectively the growth of C. albicans; G. pullulans,
M. australis, and Pseudogymanoascus sp. 1 were selective

against C. krusei. Pseudogymnnoascus sp. 2 displayed 95 %


antifungal activity against the target C. sphaerospermum,
which was approximately the same value of the control drug
benomyl (94.5 % of inhibition). The extract of Penicillium
steckii inhibited 96 % of yellow fever virus, which was much
better than the control interferon alpha (IFN-) (68 %)
(Furbino et al. 2014).
Metabolites produced from seaweed-associated fungi include aromatic polyketides, alkaloids, sesquiterpenes, and
terpenes (Osterhage et al. 2000, 2002; Bugni and Ireland
2004; Gao et al. 2011a, b, c; Oliveira et al. 2012). In general,
metabolites derived from fungi associated with green seaweeds (such as Coniothyrium cereal, Chaetomium sp., and
Penicillium sp.) are reported to contain bicyclical structures
with oxygenations or even aromatic moieties and showed cytotoxicity, antiprotozoal, antimicrobial activities, and protection from DNA damage (Gamal-Eldeen et al. 2009; Zhu et al.
2009; Elsebai et al. 2010). Metabolites derived from fungi
associated with brown seaweeds (such as Aspergillus niger
and Aspergillus ochraceus) demonstrated a greater structural
diversity and included compounds with naphto- and pyrone
derivatives exhibiting antifungal and antioxidant activities
(Zhang et al. 2007; 2010), antioxidant benzodiazepine derivatives (Cui et al. 2009), and ergosterolide derivates with an
unusual pentalactone B-ring exhibiting cytotoxic activity (Cui
et al. 2010). Metabolites derived from fungi associated with
red seaweeds (such as Aspergillus spp., Curvularia sp.,
Drechslera dematioidea, and Penicillium spp.) include
curvularin-type macrolides showing antibacterial, antifungal,
and algicide properties (Dai et al. 2011), antimicrobial
indoloterpenes (Qiao et al. 2010), sesquiterpenoids with
antiplasmodial activity (Osterhage et al. 2002), antimicrobial
monoterpene, and tetracyclic diterpenes (Gao et al. 2011a).
Acremonium sp. isolated from Plocamium sp. produce aromatic pentaketides of the dihydroisocoumarins class (Pontius

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Appl Microbiol Biotechnol (2015) 99:15711586

et al. 2008a). An Epicoccum sp. associated with Fucus


vesiculosus produces a novel antioxidant epicoccone (AbdelLateff et al. 2003).
Further, we are now summarizing the potential bioactivities
of important seaweed-associated fungal strains of genera
Aspergillus and Penicillium, in view of their wide abundance
in most of the seaweeds as well as owing to their pharmaceutical and industrial applications.
Aspergillus
Aspergillus spp. are common colonizers of marine seaweeds and
produce numerous potential pharmacological compounds.
Phenylahistin (Fig. 3a) was extracted from a marine algae associated A. ustus and showed cytotoxic activity towards human
cancer cell lines (P388 cell lines) and particularly inhibited cell
cycle progression in the G2/M phase (Kanoh et al. 1997, 1999).
Later, it was found that it inhibited tubulin polymerization at a
submicromolar concentration in vivo condition via binding at the
colchicine binding site (Kanoh et al. 1999). A new isochroman
derivative, pseudodeflectusin (Fig. 3b) with cytotoxicity to human cancer lines NUGC-3, HeLa-S3, and HL-60 (LD50 values
of 49, 47, and 39 M, respectively) was obtained from
Aspergillus pseudodeflectus, an epibiont of Sargassum fusiform
(Ogawa et al. 2004). Cui et al. (2009) isolated benzodiazepine
analogue, 2-hydroxycircumdatin C from A. ochraceus derived
from brown alga Sargassum kjellmanianum and it displayed
significant antioxidant 2,2-diphenyl-1-picrylhydrazyl (DPPH)
radical-scavenging activity (IC50 9.9 M), almost 8.9-fold more
potent than that of synthetic positive control, butylated hydroxytoluene (BHT). Further, Cui et al. (2010) also isolated a rare 7norsteoid with an unusual pentalactone B-ring system, 7-Norergosterolide (Fig. 3c) from the same endophytic fungus. This
compound showed cytotoxicity against NCI-H460, SMMC7721, and SW1990 cell lines with IC50 values of 5, 7.0, and
28 g/mL, respectively (Cui et al. 2010). This fungal endophyte
also produced a new steroid derivative, 3 ,11dihydroxyergosta-8,24(28)-dien-7-one and showed cytotoxicity
Fig. 3 Some representatives of
structurally potential bioactive
isolated from seaweed-associated
fungi. a phenylahistin; b
pseudodeflectusin; c 7-Norergosterolide; d citrinal A; and e
chromanone A

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against SMMC-7721 cell line (IC50 28.0 g/mL) (Cui et al.


2010). From the culture of Aspergillus sp., (associated with
Sargassum sp.) two new terpeptin analogs were discovered
(JBIR-81 and JBIR-82) along with a known terpeptin. JBIR-81
JBIR-82 and known terpeptin were showed strong protective
activity against L-glutamate toxicity in cells with IC50 values of
0.7, 1.5, and 0.9 M, respectively. The activity was comparable
to -tocopherol (IC50 8.8 M), a representative antioxidant
(Izumikawa et al. 2010).
Li et al. (2005) extracted five bioactive compounds namely,
epoxydone, (+)-epoxydone monoacetate, gentisyl alchol, 3chlorogentisyl alcohol, and methylhydroquinone (of the class
epoxycyclohexenones and aromatic polyols) from an organic
extract of Aspergillus sp. derived from red alga Hypnea
asidana, all of which showed potent antibacterial activities
against MRSA and multidrug-resistant S. aureus with MIC
values of 12.5, 12.5, 12.5, 50.0, and 6.2 g/ mL,
respectively. Miao et al. (2012) obtained 11 compounds from
fungal endophyte Aspergillus versicolor, isolated from brown
seaweed Sargassum thunbergii and out of them only three
compounds, brevianamide M, 6,8-di-O-methylaverufin, and
6-O-methylaverufin showed antibacterial activities against
E. coli and S. aureus. Recently, Suja et al. (2014) showed that
the purified fractions F7 and F8 of ethyl acetate extract obtained from A. terrus displayed cytotoxicity against HepG2 cancer
cell lines. The fractions F7 and F8 were shown growth inhibition (GI50), total growth inhibition (TGI), and ethality
(LC50) with <10, >10, >80,>80, and >80>80 respectively.
Penicillium
Marine-derived Penicillium is also an important source of pharmacologically active metabolites. Zhu et al. (2009) obtained
citrinal A, along with two other previously known compounds
( c i t r i n i n a n d 2, 3 , 4 - t r i m e t hyl- 5,7 -dih yd roxy -2, 3dihydrobenzofuran) from Penicillium sp. isolated from a green
alga Blidingia minima. The study particularly determined structure and stereochemistry of citrinal A which is a novel tricyclic

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compound with a rare tetrahydro-2H-benzofuro[7-b][1,4]dioxin9(3H)-one skeleton (Fig. 3d) and showed cytotoxicity against A549 (IC50 80.7 mol/L) and HL-60 cell lines (IC50 143.1 mol/
L). Gamal-Eldeen et al. (2009) isolated a new chromone derivative, chromanone A [2-(hydroxymethyl)-8-methoxy-3-methyl4H-chromen-4-one] (Fig. 3e) from Penicillium sp. associated
with Ulva sp., that exhibits anti-tumorigenesis properties via
modulation of carcinogen metabolizing enzymes (such as
NADPH-cytochrome P-450 (NADPH-CYP) reductase or isozymes of CYP or glutathione S-transferases) and protection from
DNA damage.
Gao et al. (2011a) extracted several tetracyclic diterpenes,
conidiogenones from Penicillium chrysogenum QEN-24S associated with red alga Laurencia sp., of which conidiogenone B
showed potent activity against methicillin resistant S. aureus,
Staphylococcus epidermidis, P. aeruginosa, and P. fluorescens
(each with a MIC value of 8 g/mL) along with a week antifungal activity against C. albicans (MIC, 128 mg/mL) whereas
conidiogenol showed activity against P. fluorescens and
S. epidermidis (each with a MIC value of 16 g/mL). In another
study of chemical investigation of this fungus (P. chrysogenum
QEN-24S) led to discoveries of four new compounds, polyketide derivative penicitides A and B, 2-(2,4-dihydroxy-6methylbenzoyl)-glycerol, and penicimonoterpene. Among
them, penicitides A displayed cytotoxic activity against the
human hepatocellular liver carcinoma, HepG2 cell line (IC50
32 g/mL) while penicimonoterpene showed strong inhibitory
activity against plant pathogenic insect Alternaria brassicae in
dual culture test with 17 mm inhibition zone at the concentration of 20 g/disk (Gao et al. 2011b). Further, extensive spectroscopic analysis revealed two more novel polyoxygenated
steroids compounds, namely, penicisteroids A and B (Gao
et al. 2011c). Penicisteroids A is structurally unique compound
containing tetrahydroxy and C-16-acetoxy groups and showed
potent antifungal activity against A. niger with a clear inhibition
zone of 18 mm diameter at the concentration of 20 g/disk. It
also displayed selective activity against the tumor cell lines
HeLa, SW1990, and NCI-H460 with the IC50 of 15, 31, and
40 g/mL respectively.
Two pinophilins, a class of hydrogenated azaphilones along
with the co-isolated metabolite Sch 725680 were isolated from
Penicillium pinophilum associated with Ulva fasciata. These
compounds selectively inhibited the activities of mammalian
DNA polymerases (pols), A (pol g), B (pols a, d, and 3), and
Y (pols h, i, and k) families and the growth and proliferation of
several human tumor cell lines (Myobatake et al. 2012).

Bioactivities of some other seaweed associated fungal


groups
Some other fungal groups also produce potential bioactive
compounds. For instances, Osterhage et al. (2000) isolated

Appl Microbiol Biotechnol (2015) 99:15711586

ascosalipyrrolidinone A (3R,4S,5S,6S,8R,10R)-3-[1,2,4a,5,6,
7,8,8a-octahydro-3,6,8-trimethyl-2-[(E)-1-methyl-1propenyl]-1-naphthalenyl]carbonyl-5-butoxy-1,5-dihydro-5methyl- 2H-pyrrol-2-one) from endophytic obligate marine
fungus Ascochyta salicorniae associated with Ulva sp. This
compound displayed antiplasmodial activity toward
Plasmodium falciparum strains K1 (IC50 736 ng/mL) and
NF 54 (IC50 378 ng/mL). It also showed antimicrobial activity
against Bacillus megaterium (5 mm), Mycotypha
microsporum (4 mm), and Microbotryum violaceum (2 mm)
at a concentration of 50g per filter disk and inhibited tyrosine
kinase p56lck to 70 % of its activity at a concentration of
40g/mL and to 23 % at a concentration of 200g/mL.
Wang et al. (2006) identified A novel 2H-benzopyran derivative, chaetopyranin exhibiting moderate DPPH radical scavenging activity (IC50 35 g/mL) and a weak to moderate cytotoxic activities against three tumor cell lines human microvascular endothelial cells, HMEC (IC50 15.4 g/mL), hepatocellular carcinoma cells, SMMC 7221 (IC50 28.5 g/mL), and
human lung epithelial cells, A549 (IC50 39.1 g/mL). This
compound was isolated from Chaetomium globosum derived
from Polysiphonia urceolata (Wang et al. 2006).
Naganuma et al. (2008) reported 1-deoxyrubralactone, a
novel specific inhibitor of families X (rat pol ) and Y (human
pol ) of eukaryotic DNA polymerases from a fungal strain
derived from sea algae. Its IC50 values on family X and
family Y were 11.9 and 59.8 M, respectively. Pontius et al.
(2008b) isolated a novel heterodimeric chromanone compound,
noduliprevenone exhibiting cancer chemopreventive potential
from algal endophytic fungus Nodulisporium sp. This compound contained two uniquely modified xanthone-derived
units, including four chiral centers and a chiral axis. This compound was found to be a competitive inhibitor of cytochrome
(P450) 1A activity with an IC50 value 6.51.6 M and induced
at the same time twofold NAD(P)H:quinone reductase (QR)
activity in Hepa 1c1c7 mouse culture cells with a concentration
of 5.31.1 M. Pontius et al. (2008c) also isolated two dimeric
xanthone derivatives, monodictyochromes A and B from
algicolous fungus Monodictys putredinis. Both these compounds displayed cancer chemopreventive potential and
inhibited cytochrome (P450) 1A activity with IC50 values of
5.3 and 7.5 M, respectively, as well as aromatase inhibitory
activity, with IC50 values of 24.4 and 16.5 M. In addition, they
displayed moderate activity as inducers of QR in cultured
mouse Hepa 1c1c7 cells, with CD values (concentration required to double the specific activity of QR) of 22.1 and
24.8 M, respectively. Moreover, Thirunavukkarasu et al.
(2011) and Suryanarayanan et al. (2012b) showed that fungal
endosymbionts of seaweeds (such as Alternaria, Chaetomium,
Cladosporium, Colletotrichum, Curvularia, Nigrospora,
Paecilomyces, Phaeotrichoconis, Phoma, and Pithomyces are
a good source of the therapeutic enzyme L-asparaginase which
is used in the treatment of acute lymphoblastic leukemia.

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Biotechnology approach for finding new potential


bioactive products
It is known that 99 % of the microorganisms present in natural
environments are not willingly culturable (Ward et al. 1990;
Handelsman 2004; Streit et al. 2004) and many favorable
reasons has suggested for this cause (Simu and Hagstrom
2004). Thus, it can be concluded that majority of microorganisms are not accessible for phylogenetic and functional analysis using classical culture-dependent methods (Ward et al.
1990; Handelsman 2004; Krohn-Molt et al. 2013). Recent
advances in nucleic acid-based techniques and sequence technologies have endorsed for the diversity and functional analysis of bacteria within a microbial community without the use
of laborious microscopy techniques (Rastogi and Sani 2011).
These advancements have led to identify several novel enzymes from diverse sources including the green alga
U. australis associated with bacterial communities (Yung
et al. 2011; Schallmey et al. 2011; Chow et al. 2012) and
antibiotics such as terragine, acyltyrosines, turbomycin A
and B (Brady and Clardy 2000; Wang et al. 2000; Gillespie
et al. 2002). Even, application of such techniques has greatly
been enhanced for identification of seaweed-associated microbial communities and functional analysis of associated communities (Penesyan et al. 2010, 2013b; Burke et al. 2011;
Bondoso et al. 2013; Hollants et al. 2013). For instance, using
metagenomic approach, a biosynthetic gene cluster of antifungal drug tambjamineYP1 was successfully determined in
P. tunicata associated with U. australis via constructed
E. coli fosmid library (Burke et al. 2007). Notably, this bacterial genus is also known for various biological activities as
aforementioned. Furthermore, functional genomics-based
studies of bioactives from bacteria derived from diverse
sources represent a powerful tool for identifying novel pharmaceutical drugs.
Frequency of metagenomic clones was significantly low
due to heterologous expression of clone libraries in different
host (Uchiyama and Miyazaki 2009; Ekkers et al. 2012) or
toxic effect of cloned genes (Kimelman et al. 2012). However,
it is also mentioned that such screening are targeted and likelihood gene of interest may not be distributed in all the members of particular communities (Uchiyama and Miyazaki
2009; Penesyan et al. 2013a). For example, only three clones
of the green alga U. australis associated bacteria showed antifungal activity against C. albicans out of 884 clones (Burke
et al. 2007). Recently, Penesyan et al. (2013b) developed 2880
fosmid clone libraries using DNA of six bacterial strains
which were previously obtained from green alga U. australis
and red alga D. pulchra, already known to have antibacterial
activities. Subsequently, these clones were screened for antibacterial and antinematode activities. Out of them, 13 clones
produced compounds or enzymes with antibacterial and
antinematode activities. The results of this study suggest that

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a pre-selection of bioactive-producing genomes could help in


improving the hit-rates in metagenomic screening.
Despite low hit rate of functional metagenomic analysis for
searching bioactive compounds from diverse sources, it can be
improved by using appropriate host strains, e.g., some similarities between codon uses and the presence of common biosynthetic pathway for particular metabolites of host and clone
libraries (Butzin et al. 2010; Penesyan et al. 2013b).
Additionally, Foerstner et al. (2008) employed metagenomics
Shotgun Data for identifying novel genes of type I polyketide
synthases and non-ribosomal peptide synthetases (NRPS).
These genes are found to be generally constituted part of biosynthetic pathways of production of bioactive compounds
(Foerstner et al. 2008), and it enhances the chance of hit rate
in metagenomic screening. Recently, a clone, 19 F10 of
Penesyan et al. (2013b) study was shown sequence similarity
to NRPS gene and homology with the NRPS gene indC from
Erwinia chrysanthemi (Reverchon et al. 2002), and bpsA from
Streptomyces lavendulae (Takahashi et al. 2007). Despite these few successes, there is still a serious need for the advancement of the metagenomic approach where heterologous gene
expression barrier can be overcome and hit rate can be
increased.

Conclusions and future directions


Marine environment and organisms are potential sources of
bioactive compounds, and the exploration of seaweedassociated microbes promises to deliver novel bioactives with
potential pharmaceutical applications. Unique seaweedmicrobial interaction has attracted a large group of researchers
for understanding their chemical interactions and studies of
microbial communities. Development of new tools and techniques significantly contribute to the discovery of next-generation, bioactive compounds. Metagenomic (including functional metagenomics) approaches for exploring bioactive
compounds form seaweed-associated microorganism is still
in its infancy, due to low hit ratio and heterologous gene expression in foreign host. These high-throughput genomic approaches will surely help in identifying novel metabolites
from uncultivable seaweed-associated microbes. Notably,
there is a requirement to improve such technique to overcome
barrier of heterologous expression. Probably, choosing appropriate host and highly expected clone sources of bioactive
producers.
So far, a number of novel bioactive compounds have been
obtained from seaweed-associated bacterial and fungal
sources, which represent seaweed as another hub of novel
marine derived natural products, despite there are several studies which only screened microorganism for antimicrobial
compounds without identified potential molecules
(Suryanarayanan et al. 2010, 2012; Suryanarayanan 2012;

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1582

Suryanarayanan et al. 2012; Suvega and kumar 2014).


Seaweed-associated microbes provide unique and novel metabolites of unprecedented structures, with antibacterial, antifungal, antiviral, antiplasmodial, nematicidal, anti-inflammatory, anticancer, and antiangiogenic activities. Thus, these bioactive compounds may provide high-quality drug candidates
for pharmaceutical applications, as well as agricultural and
industrial applications. Therefore, the exploration of
seaweed-associated microbes using new tools and techniques,
such as those of high-throughput genomic and metagenomic
approaches, will led to the discovery of more novel bioactive
natural products in future, and will help in exploiting their
biotechnological potential
Acknowledgments CSIR is gratefully acknowledged for awarding the
Senior Research Fellowship (SRF) to R.P. Singh and P. Kumari. CSIRCSMCRI also thanked for facilities and encouragement provided while
preparing this manuscript.

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