Pharmaceutically Active Secondary Metabolites of Marine Actinobacteria

Microbiological Research 169 (2014) 262278
Contents lists available at ScienceDirect
Microbiological Research
journal homepage: www.elsevier.com/locate/micres
Review
Pharmaceutically active secondary metabolites of marine

actinobacteria
Panchanathan Manivasagan a , Jayachandran Venkatesan a , Kannan Sivakumar c ,
Se-Kwon Kim a,b,
a
Marine Biotechnology Laboratory, Department of Chemistry, Pukyong National University, Busan 608-737, Republic of Korea
Marine Bioprocess Research Center, Pukyong National University, Busan 608-737, Republic of Korea
c
Centre of Advanced Study in Marine Biology, Faculty of Marine Sciences, Annamalai University, Parangipettai 608 502, Tamil Nadu, India
b
a r t i c l e
i n f o
Article history:
Received 4 May 2013
Received in revised form 29 June 2013
Accepted 22 July 2013
Available online 16 August 2013
Keywords:
Marine actinobacteria
Antibiotics
Bioactive compounds
Secondary metabolites
a b s t r a c t
Marine actinobacteria are one of the most efcient groups of secondary metabolite producers and are very
important from an industrial point of view. Many representatives of the order Actinomycetales are prolic producers of thousands of biologically active secondary metabolites. Actinobacteria from terrestrial
sources have been studied and screened since the 1950s, for many important antibiotics, anticancer, antitumor and immunosuppressive agents. However, frequent rediscovery of the same compounds from the
terrestrial actinobacteria has made them less attractive for screening programs in the recent years. At the
same time, actinobacteria isolated from the marine environment have currently received considerable
attention due to the structural diversity and unique biological activities of their secondary metabolites.
They are efcient producers of new secondary metabolites that show a range of biological activities
including antibacterial, antifungal, anticancer, antitumor, cytotoxic, cytostatic, anti-inammatory, antiparasitic, anti-malaria, antiviral, antioxidant, anti-angiogenesis, etc. In this review, an evaluation is made
on the current status of research on marine actinobacteria yielding pharmaceutically active secondary
metabolites. Bioactive compounds from marine actinobacteria possess distinct chemical structures that
may form the basis for synthesis of new drugs that could be used to combat resistant pathogens. With the
increasing advancement in science and technology, there would be a greater demand for new bioactive
compounds synthesized by actinobacteria from various marine sources in future.
2013 Elsevier GmbH. All rights reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Marine actinobacteria as a novel source of bioactive compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Secondary metabolites from marine actinobacteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Antibacterial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Antifungal activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Antitumor activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.5.
Cytotoxic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.6.
Cytostatic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.7.
Anti-inammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.8.
Anti-parasitic activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.9.
Anti-malarial activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.10.
Antiviral activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.11.
Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.12.
Anti-angiogenesis activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
This article is part of a Special Issue entitled Medicinal Extracts in Microbiology.

Corresponding author. Tel.: +82 10 7131 8218; fax: +82 51 629 7099.
E-mail addresses: sknkim@pknu.ac.kr, manimaribtech@gmail.com (S.-K. Kim).
0944-5013/$ see front matter 2013 Elsevier GmbH. All rights reserved.
http://dx.doi.org/10.1016/j.micres.2013.07.014
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P. Manivasagan et al. / Microbiological Research 169 (2014) 262278
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Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276
1. Introduction
New drugs, especially antibiotics, are urgently needed to
counter and reverse the spread of antibiotic resistant pathogens
(Payne et al. 2006; Talbot et al. 2006) and to combat life-threatening
diseases such as cancer (Olano et al. 2009). Although considerable
progress is being made within the elds of chemical synthesis and
engineered biosynthesis of antimicrobial compounds, nature still
remains the richest and the most versatile source for new antibiotics (Koehn and Carter 2005; Baltz 2006; Pelez 2006).
Actinobacteria, which are the prolic producers of antibiotics and important suppliers to the pharmaceutical industry, can
produce a wide variety of secondary metabolites (Baltz 2005).
Actinobacteria belonging to the family Actinomycetaceae are well
known for their ability to produce secondary metabolites many of
which are active against pathogenic microorganisms. Traditionally, these bacteria have been isolated from terrestrial sources,
although the rst report of mycelium-forming actinobacterium
from the marine sediments appeared several decades ago (Weyland
1969). It is only more recently that marine actinobacteria have
become recognized as a source of novel antibiotics and anticancer agents with unusual structures and properties (Jensen et al.
2005).
Marine actinobacteria are the best sources of secondary metabolites and the vast majority of these compounds are derived from the
single genus Streptomyces, whose species are distributed widely
in the marine and terrestrial habitats (Pathom-Aree et al. 2006a)
and are of commercial interest due to their unique capacity
to produce novel metabolites. It was also perceived that Streptomyces species will have a cosmopolitan distribution, as they
produce abundant spores that are readily dispersed (Antony-Babu
et al. 2008) and these lamentous bacteria are well adapted to
the marine environment and can break down complex biological polymers (Anderson and Wellington 2001). In fact, the genus
Streptomyces alone accounts for a remarkable 80% of the actinobacterial natural products reported to date, a biosynthetic capacity
that remains without rival in the microbial world (Watve et al.
2001).
Marine actinobacteria are widely distributed in biological
sources such as shes, molluscs, sponges, seaweeds, mangroves,
besides seawater and sediments. These organisms are gaining
importance not only for their taxonomic and ecological perspectives, but also for their production of novel bioactive compounds
like antibiotics, antitumor agents, immunosuppressive agents,
enzymes, enzyme inhibitors, pigments (Dharmaraj 2010). In this
review we focuses on novel bioactive compounds identied from
marine actinobacteria and classied them in terms of their chemical structure, covering the literature to date.
2. Marine actinobacteria as a novel source of bioactive
compounds
Marine actinobacteria are the most economically and biotechnologically priceless prokaryotes. Representative genera of
actinobacteria include Streptomyces, Actinomyces, Arthrobacter,
Corynebacterium, Frankia, Micrococcus, Micromonospora and several
others. Secondary metabolites produced by the marine actinobacteria possess a wide range of biological activities (Oldeld et al.
1998; Mann 2001; Berdy 2005; Manivasagan et al. 2013). The
genus Streptomyces alone produces a large number of bioactive
molecules. It has an enormous biosynthetic potential that remains

unchallenged without a potential competitor among other microbial groups. A large number of Streptomyces spp. have been isolated
and screened from soil in the past several decades (Watve et al.
2001). Consequently, chances of isolating a novel Streptomyces
strain from terrestrial habitats have diminished. Above 500
species of Streptomyces account for 7080% of relevant secondary
metabolites, which have a wide range of activities such as antibacterial, antifungal, anticancer, antitumor, cytotoxic, cytostatic,
anti-inammatory, anti-parasitic, anti-malaria, antiviral, antioxidant and anti-angiogenesis, etc. (Table 1). Small contributions
care from other genera, such as Saccharopolyspora, Amycolatopsis,
Micromonospora and Actinoplanes. An important reason for discovering novel secondary metabolites is to circumvent the problem
of resistant pathogens, which are no longer susceptible to the
currently used drugs (Lam 2006; Ekwenye and Kazi 2007). The
number of deaths due to these clever pathogenic organisms is on
the rise. Secondary metabolites from marine actinobacteria may
form the basis for the synthesis of novel therapeutic drugs, which
may be efcient to combat a range of resistant microbes (Fenical
and Jensen 2006).
Existence of cousins of terrestrial actinobacteria has been
reported in the relatively untapped marine ecosystem. Immense
diversity of this habitat along with its underexploitation is the
fundamental reason for attracting researchers toward it for discovering novel metabolite producers. There is an occurrence of
distinct rare genera in the marine ecosystem as evidenced by the
taxonomic description of the rst marine actinobacteria Rhodococcus marinonascens (Helmke and Weyland 1984). Actinobacteria
comprise about 10% of the bacteria colonizing marine aggregates and can be isolated from marine sediments (Ward and Bora
2006). Many actinobacterial isolates from deep oceans contain nonribosomal polyketide synthetase (NRPS) and polyketide synthetase
(PKS) pathways, the hallmarks of secondary metabolite production
(Salomon et al. 2004). Actinobacteria have also been isolated from
free swimming as well as sessile marine vertebrates and invertebrates (Ward and Bora 2006). Unusual actinobacteria belonging
to Micrococceae, Dermatophilaceae and Gordoniaceae, have been
isolated from sponges (Lam 2006). Tetrodotoxin-producing actinobacteria most closely related to Nocardiopsis dassonvillei have
been isolated from puffer sh ovaries (Wu et al. 2005).
Researchers are nding new genera from marine environments on a regular basis and discovering new metabolite
producers never reported earlier. Actinobacteria genera identied by cultural and molecular techniques from different marine
ecological niches include Actinomadura, Actinosynnema, Amycolatopsis, Arthrobacter, Blastococcus, Brachybacterium, Corynebacterium, Dietzia, Frankia, Frigoribacterium, Geodermatophilus, Gordonia, Kitasatospora, Micromonospora, Micrococcus, Microbacterium,
Mycobacterium, Nocardioides, Nocardiopsis, Nonomurea, Psuedonocardia, Rhodococcus, Saccharopolyspora, Salinispora, Serinicoccus,
Solwaraspora, Streptomyces, Streptosporangium, Tsukamurella, Turicella, Verrucosispora and Williamsia (Ward and Bora 2006). In spite
of the improvements being made in the cultural methods for the
isolation of rare marine actinobacteria, many of these organisms
still remain unculturable and have to be detected by using molecular techniques (Stach et al. 2003; Mincer et al. 2005). Metagenomic
methods, therefore will be useful for characterizing microbes that
cannot be cultivated and can also be used to isolate their genes
(Tringe et al. 2005).
264
Table 1
Novel secondary metabolites produced by marine actinobacteria.
Compound
Species
Other biological
activity
Reference
Antibacterial activity
Abyssomicins
Bonactin
Chloro-dihydroquinones
Diazepinomicin
Verrucosispora sp.
Streptomyces sp.
Streptomyces sp.
Micromonosproa sp.
Antifungal
Anticancer
Anticancer;
anti-inammatory
Cytotoxic
Cytotoxic
Antifungal; anticancer
Riedlinger et al. (2004)

Schumacher et al. (2003)
Soria-Mercado et al. (2005)
Charan et al. (2004)
Maskey et al. (2003b)
Frigocyclinone
Essramycin
Lynamicins
Marinopyrroles
Caboxamycin
Himalomycins
Marinomycins
Glyciapyrroles
Tirandamycin
Bisanthraquinone
Gutingimycin
Helquinoline
Lajollamycin
TP-1161
Lincomycin
Tirandamycins
1,4-Dihydroxy-2-(3-hydroxybutyl)-9,10anthraquinone
9,10-anthrac
Antifungal activity
Chandrananimycin
Streptomyces griseus
Streptomyces sp.
Marinispora sp.
Streptomyces sp.
Streptomyces sp.
Streptomyces sp.
Marinispora
Streptomyces sp.
Streptomyces sp.
Streptomyces sp.
Streptomyces sp.
Janibacter limosus
Streptomyces nodosus
Nocardiopsis sp.
Streptomyces lincolnensis
Streptomyces sp.
Streptomyces sp.
N-(2-hydroxyphenyl)-2-phenazinamine (NHP)
Anticancer activity
Salinosporamide A
Caprolactones
3,6-Disubstituted indoles
IB-00208
1-Hydroxy-1-norresistomycin
Nocardia dassonvillei.
Antialgal;
antibacterial;
anticancer
Anticancer
Salinispora tropica
Streptomyces sp.
Streptomyces sp.
Actinomadura sp.
Streptomyces chinaensis
Antibacterial
ZHD-0501
Antitumor activity
Chinikomycins
Glyciapyrroles
Mechercharmycin A
Aureoverticillactam
Arenicolides
Chalcomycin
Daryamides
Aureolic acid
1,8-Dihydroxy-2-ethyl-3-methylanthraquinone
Arenimycin
Mitomycin C
Staurosporinone
Streptokordin
Elaiomycins B and C
Cytotoxic activity
Manumycins
Salinipyrones
Pacicanones
Actinofuranones
Nonactin
Resistoavine
Neomarinones
Piericidins
Lucentamycins
Arenamides
Piperazimycins
Mansouramycin C
Usabamycins
Pyridinium
ML-449 (macrolactam)
Salinosporamide B & C
Albidopyrone
Actinomadura sp.
Feling et al. (2003)

Stritzke et al. (2004)
Lpez et al. (2003)
Rodriguez et al. (2003)
Gorajana et al. (2005) and
Kock et al. (2005)
Han et al. (2003)
Streptomyces sp.
Streptomyces sp.
Thermoactinomyces sp
Streptomyces aureoverticillatus
Salinispora arenicola
Streptomyces sp.
Streptomyces sp.
Streptomyces sp.
Streptomyces sp.
Salinispora arenicola
Streptomyces lavendulae
Streptomyces sp.
Streptomyces sp.
Streptomyces sp.
Antibacterial;
Phycotoxicity
Li et al. (2005)
Macherla et al. (2005)
Kanoh et al. (2005)
Mitchell et al. (2004)
Williams et al. (2007)
Wu et al. (2007)
Asolkar et al. (2006)
Lu et al. (2012)
Huang et al. (2006)
Mao et al. (1999)
Wu et al. (2006)
Jeong et al. (2006)
Helaly et al. (2011)
Streptomyces sp.
Salinispora pacica
Salinispora pacica
Streptomyces
Streptomyces sp.
Streptomyces chibaensis
Actinomycetales
Streptomyces sp.
Nocardiopsis lucentensis
Salinipora arenicola
Streptomyces sp.
Streptomyces sp.
Streptomyces sp.
Amycolatopsis alba.
Streptomyces sp.
Salinipora tropica
Streptomyces sp.
Antimicrobial
Cytotoxic (inhibitor of
proteintyrosine
phosphatise)
Chauhan et al. (2005)

Oh et al. (2008)
Oh et al. (2008)
Cho et al. (2006)
Jeong et al. (2006)
Gorajana et al. (2007)
Hardt et al. (2000)
Hayakawa et al. (2007a,b)
Cho et al. (2007)
Miller et al. (2007)
Hawas et al. (2009)
Sato et al. (2011)
Dasari et al. (2012)
Jrgensen et al. (2010)
Williams et al. (2005)
Hohmann et al. (2009b)
Actinomadura sp.
Bruntner et al. (2005)

El-Gendy et al. (2008)
McArthur et al. (2008)
Hughes et al. (2008)
Hohmann et al. (2009a)
Maskey et al. (2003a)
Kwon et al. (2006)
Macherla et al. (2005)
Carlson et al. (2009)
Socha et al. (2006)
Maskey et al. (2004a)
Manam et al. (2005)
Engelhardt et al. (2010)
Peschke et al. (2006)
Carlson et al. (2009)
Ravikumar et al. (2012b)
Gao et al. (2012)
265
Table 1 (Continued )
Compound
Cytostatic activity
Proximicins
Anti-inammatory activity
Cyclomarins
Salinamides A and B
Anti-parasitic activity
Avermectins
Anti-malarial activity
Trioxacarcin
Anti viral activity
Benzastatin C
Antioxidant activity
Dermacozines A-G
Lipocarbazoles
2-Allyloxyphenol
Anti-angiogenesis activity
Streptopyrrolidine
Cyclo-(l-Pro-l-Met)
Species
Other biological
activity
Reference
Verrucosispora sp.
Schneider et al. (2008)
Streptomyces sp.
Salinispora
Arenicola
Streptomyces sp.
Renner et al. (1999)

and Schultz et al.
(2008)
Moore et al. (1999)
Streptomyces avermitilis
Burg et al. (1979)
Streptomyces sp.
Antibacterial;
antitumor
Maskey et al. (2004b)
Streptomyces nitrosporeus
Lee et al. (2007)
Dermacoccus
Abdel-Mageed et al. (2010)
Tsukamurella pseudospumae
Streptomyces sp.
Antitumor;
Antiprotozoal
Antimicrobial
Streptomyces sp.
Nocardiopsis sp.
Shin et al. (2008)

Shin et al. (2010)
3. Secondary metabolites from marine actinobacteria

Marine actinobacteria are known to have the ability to produce
a wide variety of secondary metabolites. Indeed, each strain of actinobacteria is likely to have the genetic potential for the production
of 1020 secondary metabolites (Bentley et al. 2002; Lam 2006).
About 23,000 antibiotics have been discovered from microorganisms. It has been estimated that approximately 10,000 of them have
been isolated from actinobacteria. Actinobacteria, mainly the genus
Streptomyces, have the ability to produce a wide variety of secondary metabolites as bioactive compounds, including antibiotics.
The group has an enormous biosynthetic potential that remains
unchallenged among other microbial groups. The immense diversity, along with its underutilization is the fundamental reason for
attracting the researchers toward discovering novel metabolites. A
schematic representation of steps followed to develop a pharmaceutical agent has been presented in Fig. 1.
3.1. Antibacterial activity
An antibacterial substance is an agent that inhibits bacterial
growth or kills bacteria. Infectious diseases remain one of the
main causes of death due to antibiotic resistant microorganisms
(Ravikumar et al. 2012b). Frequency of resistance in microbial
pathogens continues to grow at an alarming rate throughout the
world (Ravikumar et al. 2010b). Decreased efcacy and resistance
of pathogens to antibiotics and it has necessitated development
of new alternatives (Ravikumar et al. 2010b). To overcome this
problem, development of effective newer drugs without any side
effects is an urgent need.
In general, marine actinobacteria are extensively studied for
antibacterial activity. Abyssomicin C (1) (Fig. 2) is a novel polycyclic
polyketide antibiotic produced by a marine Verrucosispora strain
(Riedlinger et al. 2004). It is a potent inhibitor of para-aminobenzoic
acid biosynthesis and, therefore, inhibits the folic acid biosynthesis
at an earlier stage than the well-known synthetic sulfa drugs (Bister
et al. 2004). Abyssomicin C possesses potent activity against Grampositive bacteria, including clinical isolates of multiple-resistant
and vancomycin-resistant Staphylococcus aureus. Abyssomicin C or
its analog (Rath et al. 2005) has the potential to be developed as
antibacterial agent against drug-resistant pathogens.
A new compound, assigned the trivial name bonactin (2) (Fig. 2),
has been isolated from the liquid culture of a Streptomyces sp.
Schneider et al. (2009)

Arumugam et al. (2010)
BD21-2, obtained from a shallow-water sediment sample collected

at Kailua Beach, Oahu, Hawaii. Bonactin displayed antimicrobial
activity against both Gram-positive and Gram-negative bacteria
as well as antifungal activity (Schumacher et al. 2003). Chlorinated dihydroquinones (3) (Fig. 2) are novel antibiotics produced
by a new marine Streptomyces sp. (Soria-Mercado et al. 2005).
The compounds formally possess new carbon skeletons, but are
related to several previously reported metabolites of the napyradiomycin class. Structures of the new molecules possess signicant
antibacterial and cancer cell cytotoxicities. Diazepinomicin (4)
(Fig. 2) is an unique farnesylated dibenzodiazepinone produced by
a Micromonospora strain (Charan et al. 2004). It possesses antibacterial, anti-inammatory and antitumor activity. It has a broad
spectrum of in vitro cytotoxicity and has demonstrated in vivo
activity against glioma, breast and prostate cancer in mouse models. Frigocyclinone (5) (Fig. 2) is a new angucyclinone antibiotic
isolated from Streptomyces griseus strain NTK 97, consisting of a
tetrangomycin moiety attached through a C-glycosidic linkage with
the aminodeoxysugar ossamine. Frigocyclinone showed antibacterial activities against Gram-positive bacteria (Bruntner et al.
2005).
Essramycin (6) (Fig. 2) is a novel triazolopyrimidine antibiotic
isolated from Streptomyces sp. The compound is antibacterially
active with MIC of 28 g/mL against Gram-positive and Gramnegative bacteria (El-Gendy et al. 2008). Lynamicins (7) (Fig. 3) are
chlorinated bisindole pyrroles, isolated from Marinispora sp. The
antimicrobial spectrum of these compounds was evaluated against
a panel of 11 pathogens, which demonstrated that these substances
possess broad-spectrum activity against both Gram-positive and
Gram-negative organisms. Signicantly, compounds were active
against drug-resistant pathogens such as methicillin-resistant S.
aureus and vancomycin-resistant Enterococcus faecium (McArthur
et al. 2008). Marinopyrroles (8) (Fig. 3) are densely halogenated
and axially chiral metabolites that contain an uncommon bispyrrole structure isolated from Streptomyces sp. The marinopyrroles
possess potent antibiotic activities against methicillin-resistant S.
aureus (Hughes et al. 2008).
Caboxamycin (9) (Fig. 3) is a new benzoxazole antibiotic and was
detected by HPLC-diode array screening in extracts of Streptomyces
sp. NTK 937, another strain which was isolated from the sediments
collected from the Canary Basin. The compound, caboxamycin was
named after the rst letters of the collection site from where the
organism was isolated and from letters drawn from its chemical
266
Fig. 1. Flow chart depicting the main techniques of isolation and culture of marine actinobacteria, extraction of compound and its chemical and biological characterization
leading to the development of a pharmaceutical product.
structure. Caboxamycin showed inhibitory activity against both

Gram-positive bacteria and against the tumor cell lines gastric adenocarcinoma (AGS), hepatocellular carcinoma (Hep G2) and breast
carcinoma cells (MCF7). The antibiotic also showed an inhibitory
activity against the enzyme phosphodiesterase (Hohmann et al.
2009a). Himalomycins A (10) and B (11) (Fig. 3) are anthracycline
antibiotics. They were obtained from Streptomyces sp. 6921, isolated from the marine sediments of Mauritius and exhibited strong
antibacterial activity (Maskey et al. 2003a). Glyciapyrroles A (12),
B (13) and C (14) (Fig. 4) are a new pyrrolosesquiterpenes antibiotics isolated from Streptomyces sp. NPS008187. The exhibited
antibacterial activity (Macherla et al. 2005). Tirandamycin C (15)

(Fig. 4) is a novel dienoyl tetramic acids isolated from Streptomyces
sp. 307-9. Tirandamycin C showed inhibitory activity against
vancomycin-resistant Enterococcus faecalis (Carlson et al. 2009).
Bisanthraquinone (16) (Fig. 4) is a new antibiotic isolated from
Streptomyces sp. Biological activities were measured against clinically derived isolates of vancomycin-resistant E. faecium (VRE), and
methicillin-susceptible, methicillin-resistant, and tetracyclineresistant S. aureus (MSSA, MRSA, and TRSA, respectively). The most
potent antibiotic displayed MIC50 values of 0.11, 0.23, and 0.90 M
against a panel (n = 25 each) of clinical MSSA, MRSA and VRE,
267
Fig. 2. Chemical structure of Abyssomicin C, Bonactin, Chlorinated dihydroquinones, Diazepinomicin, Frigocyclinone and Essramycin.
respectively, and was determined to be bactericidal by time-kill

analysis (Socha et al. 2006).
3.2. Antifungal activity
Numerous antibiotics have been isolated from a variety of
microorganisms; however, studies are still being conducted to
identify novel antibiotics effective against pathogenic fungi (Atlas
and Bartha 1986). Marine actinobacteria are useful biological tools
for the production of antifungal substances against fungi (Okami
and Hotta 1988). In general, Streptomyces species are saprophytic
and are commonly associated with soils, where they contribute signicantly to the turnover of complex biopolymers and antibiotics
(Wanner 2009). Marine Streptomyces sp. DA11 isolated from South
China, found to be associated with sponge Craniella australiensis,
produced the enzyme chitinase and showed antifungal activities

against Aspergillus niger and Candida albicans (Han et al. 2009).
Chitin, a linear -1,4-linked homopolymer of N-acetylglucosamine,
is one of the three most abundant polysaccharides in nature besides
cellulose and starch. The antifungal activity and highly biocompatible quality make chitinase and its derivatives particularly useful for
biomedical applications, such as wound healings, cartilage tissue
engineering, drug delivery, and nerve generation (Shi et al. 2006;
Yan et al. 2006). The biodegradable and antifungal properties of
chitinase are also useful for environmental and agricultural uses,
food technology and cosmetics (Rabea et al. 2003; Lin and Lin 2005).
Chandrananimycin A (17) (Fig. 4) is a novel antibiotic isolated from Actinomadura sp. Chandrananimycin A possesses potent
antifungal activity against Mucor miehei. It also exhibits antialgal activity against the microalgae Chlorella vulgaris and Chlorella
Fig. 3. Chemical structure of Lynamicins, Marinopyrroles, Caboxamycin, Himalomycin A and Himalomycin B.
268
Fig. 4. Chemical structure of Glyciapyrroles A, Glyciapyrroles B, Glyciapyrroles C, Tirandamycin C, Bisanthraquinone and Chandrananimycin A.
sorokiniana and antibacterial activity against S. aureus and Bacillus

subtilis, along with anticancer activity (Maskey et al. 2003b). N(2-hydroxyphenyl)-2-phenazinamine (NHP) (18) (Fig. 5) is a new
antibiotic isolated from Nocardia dassonvillei. The new compound
showed signicant antifungal activity against C. albicans, with a MIC
of 64 g/mL and high cancer cell cytotoxicity against HepG2, A549,
HCT-116 and COC1 cells (Gao et al. 2012).
3.3. Anticancer activity
Cancer still remains one of the most serious human health problems and breast cancer is the second most universal cause of cancer
deaths in women (Ravikumar et al. 2010a). Therapeutic methods
for cancer treatment are surgery, radiotherapy, immunotherapy
and chemotherapy (Gillet et al. 2007) and these techniques are
individually useful in particular situations and when combined,

they offer a more efcient treatment for tumor. Many of the
antitumor compounds from marine drugs are derived from marine
actinobacteria and these metabolites play an important role in
identication of pharmaceutical compounds (Ravikumar et al.
2012a). Currently, it appears that there have been only a few
studies focusing on nding bioactive compounds derived from
marine actinobacteria to be used as anticancer agents, as well as
agents against infectious organisms.
Pure active compounds extracted from the marine actinobacterium, Salinispora tropica have shown inhibitory effects in many
malignant cell types (Prudhomme et al. 2008). In particular, Salinosporamide A (19) (Fig. 5) is a novel rare bicyclic beta-lactone
gamma-lactam isolated from an obligate marine actinobacterium,
S. tropica (Feling et al. 2003; Jensen et al. 2007). Salinosporamide A is
Fig. 5. Chemical structure of N-(2-hydroxyphenyl)-2-phenazinamine (NHP), Salinosporamide A, Caprolactones, Chinikomycin A, Marinomycins and Aureoverticillactam.
an orally active proteasome inhibitor that induces apoptosis in multiple myeloma cells with mechanisms distinct from the commercial
proteasome inhibitor anticancer drug Bortezomib (Chauhan et al.
2005). It is being developed by Nereus Pharmaceuticals, Inc. (as NPI0052) and was scheduled to enter clinical studies for treatment of
cancer in humans in 2006. NPI-0052 is currently being evaluated
in multiple phase I trials for solid tumors, lymphoma and multiple myeloma (http://www.nereuspharm.com/NPI-0052.shtml).
NPI-0052 represents the rst clinical candidate for the treatment
of cancer produced by saline fermentation of an obligate marine
actinobacterium (Fenical et al. 2009).
Prudhomme et al. (2008) tested Salinosporamide A for its utility as an anticancer and antimalarial drug. It was shown to have
inhibitory activity against parasite development in vitro (Plasmodium falciparum) and in vivo (Plasmodium yoelii). The exact mode by
which salinosporamide A inhibits Plasmodium erythrocytic development is unknown; however, it is likely due to the inhibition of
the proteasome complex. It is interesting to note that chloroquine
resistant strains are still sensitive to Salinosporamide A. Targeting
the proteasome system has a huge therapeutic implication as it can
restrain growth and survival of most cell types (Prudhomme et al.
2008). These attributes, taken with the fact that it is already in phase
I clinical trials as an antitumor agent, make it an excellent candidate for alternative therapies, such as antibacterial, anti-parasitic,
antifungal or antiviral treatments. Caprolactones (20) (Fig. 5) are
new antibiotics isolated from Streptomyces sp. showing moderate
phytotoxicity and promising activity against cancer cells with concomitant low general cytotoxicity (Stritzke et al. 2004).
3.4. Antitumor activity
Thousands of antibiotics have been successfully applied to prevent and treat diseases caused by microbes in the clinical settings
over the past half-century. It is therefore no wonder that more
and more tumor cells and bacteria have developed antimicrobial
resistance or even multidrug-resistance. In the past, solution to
the problem depended primarily on the development of novel
antineoplastic and antimicrobial agents from common resources.
A great number of structurally interesting and biologically active
secondary metabolites produced by microorganisms have been
reported; many of which being exploited by the pharmaceutical industry as potent antibiotics (Bernan et al. 2004; Berdy
269
2005). However, number of these new antibiotics is noted to have

decreased dramatically in recent years due to exhaustion of common resources (Bentley et al. 2002; Demain and Sanchez 2009). In
this regard, focus on rare resources, such as marine actinobacteria,
has attracted special attention. This is due to their capability to produce biologically active secondary metabolites, with many of them
as potent antibiotics and/or lead compounds that would otherwise
not be discovered in terrestrial microorganisms (Fenical et al. 2002;
Blunt et al. 2006; Mayer et al. 2007; Mikami 2007; Williams 2009).
Chinikomycin A (21) (Fig. 5) are a novel antitumor antibiotic
isolated from Streptomyces sp. They exhibited antitumor activity
against different human cancer cell lines, but were inactive in
antiviral, antimicrobial and phytotoxicity test (Li et al. 2005). Marinomycins (22) (Fig. 5) are new antitumor antibiotics isolated from
Marinispora sp. Marinomycins show signicant antimicrobial activities against drug resistant bacterial pathogens and demonstrate
impressive and selective cancer cell cytotoxicities against six of
the eight melanoma cell lines in the National Cancer Institutes
60 cell line panel. The discovery of these new compounds from
a new, chemically rich genus further documents that marine actinobacteria are a signicant resource for drug discovery (Kwon et al.
2006).
Aureoverticillactam (23) (Fig. 5) is a 22-membered macrocyclic
lactam produced by Streptomyces aureoverticillatus NPS001583
isolated from marine sediments. Aureoverticillactam was found
to possess moderate growth inhibitory activity against human
colorectal adenocarcnioma HT-29, Jurkat leukemia and mouse
melanoma B16F10 cell lines (Mitchell et al. 2004). A new cytotoxic substance named mechercharmycin A (24) (Fig. 6) was
isolated from marine-derived Thermoactinomyces sp. YM3-251.
Mechercharmycin A exhibited relatively strong antitumor activity, whereas mechercharmycin B exhibited no such activity (Kanoh
et al. 2005).
A higher number of type I polyketide derived compounds with
antitumor activity have been isolated from marine actinobacteria.
Once such compound is arenicolides (25) (Fig. 6), 26-membered
polyunsaturated macrolactones, produced by the obligate marine
actinobacteria Salinispora arenicola strain CNR-005, isolated from
the marine sediments, at a depth of 20 m from the coastal around
the island of Guam. In particular, arenicolide A was found to exhibit
moderate cytotoxicity toward the human colon adenocarcinoma
cell line HCT-116 with an IC50 of 30 g/mL (Williams et al. 2007).
Fig. 6. Chemical structure of Mechercharmycin A, Arenicolide, Chalcomycin and Daryamide A.
270
Fig. 7. Chemical structure of Daryamide B and C, Manumycin A, Aureolic acid and Salinipyrones A.
Chalcomycin (26) (Fig. 6), a 16-membered macrolide, is produced

by Streptomyces sp. M491 isolated from the Qingdao coast (China).
Chalcomycin has been found to inhibit protein synthesis in HeLa
human cervix carcinoma cell line (Asolkar et al. 2002).
Daryamides are new antitumor-antibiotics isolated from
marine-derived Streptomyces strain CNQ-085. Daryamides A (27)
(Fig. 6), B (28) and C (29) (Fig. 7) were subjected to cytotoxicity
evaluation against the human colon carcinoma cell line HCT-116.
Daryamide A exhibited signicantly more potent cancer cell cytotoxicity, with an IC50 of 3.15 g/mL, than daryamides B and C and
very weak antifungal activity against C. albicans (Asolkar et al.
2006). Manumycins constitute a class of compounds with antibiotic, cytotoxic, and other biological activities. It has been reported
that manumycin A (30) (Fig. 7) and its analogs inhibit Ras farnesyl
transferase and the growth of Ki-ras-activated murine brosarcoma
in mice (Sattler et al. 1998). The side chains in manumycins appear
to be a typical polyketide-derived moiety, differing with respect
to their combinations of starter and elongation units. The central
cyclohexene ring may be derived from the polyketide as in the case
of manumycins or from some modied amino acid like 3-amino5-hydroxybenzoic acid. Manumycin A and chinikomycins A and B
(the quinone form of chinikomycin A) were isolated from Streptomyces sp. M045 derived from the sediments of Jiaozhou Bay in
China (Li et al. 2005). Aureolic acid (31) (Fig. 7) (Chromomycin B,
A2 and A3 ) are a new antitumor antibiotics isolated from Streptomyces sp. WBF16. These compounds showed strong cytotoxicity
against SGC7901, HepG2, A549, HCT116 and COC1 and HUVEC (Lu
et al. 2012).
3.5. Cytotoxic activity
Four new polyketides, salinipyrones A (32) (Fig. 7) and B (33)
(Fig. 8), and pacicanones A (34) and B (35) (Fig. 8) have been
isolated from cultures of the obligate marine actinobacteria Salinispora pacica CNS-237, found in the sediments collected from the
Palau island, Western Pacic Ocean. Biological activity of these

compounds is currently being examined in diverse bioassays. In
the initial screening, salinipyrones and the pacicanones displayed
no signicant activity in a cancer cytotoxicity assay using HCT116 human colon cancer cells. In an isolated mouse splenocyte
model of allergic inammation, salinipyrone A displayed moderate
inhibition of interleukin-5 production by 50% at 10 g/mL without
measurable human cell cytotoxicity (Oh et al. 2008).
Two new polyketides, actinofuranones A (36) and B (37) (Fig. 8),
were isolated from the culture extract of a marine-derived Streptomyces strain, designated as CNQ766. It showed weak in vitro
cytotoxicity against mouse splenocyte T-cells and macrophages
with IC50 values of 20 g/mL and were inactive against human
colon carcinoma HCT-116 cells (Cho et al. 2006). Nonactin (38)
(Fig. 8), a cyclic polyether also known as macrotetrolide, has been
isolated from cultures of Streptomyces sp. KORDI-3238, isolated
from deep-sea sediments collected at Ayu Trough in the Western Pacic Ocean (Jeong et al. 2006). Biosynthesis of gene cluster
of nonactin has previously been isolated and characterized from
S. griseus DSM40695 (Smith et al. 2000), revealing that it is synthesized by a non-iteratively acting type II PKS that involves ve
ketosynthases and lacks the acyl carrier protein. Nonactin exhibited signicant cytotoxicity against the multidrug-resistant human
erythroleukemia cell line K-562 (Borrel et al. 2005). Resistoavine
(39) (Fig. 8) is a cytotoxic compound, isolated from Streptomyces
chibaensis AUBN1 /7. It showed cytotoxic activity against human
gastric adenocarcinoma HMO2 and hepatic carcinoma HePG2 cell
lines (Gorajana et al. 2007).
Neomarinones (40) (Fig. 8) are sesquiterpenoid naphthoquinones with a mixed polyketide-terpenoid origin (Pathirana et al.
1992). Neomarinone, isomarinone, hydroxydebromomarinone and
methoxydebromomarinone were produced by the actinobacterial
isolate CNH-099 obtained from sediments at 1 m depth in Batiquitos Lagoon, North of San Diego, California. These compounds
showed moderate in vitro cytotoxicity (IC50 of 8 g/mL) against
271
Fig. 8. Chemical structure of Salinipyrones B, Pacicanones A, Pacicanones B, Actinofuranone A, Actinofuranone B, Nonactin, Resistoavine and Neomarinones.
human colon carcinoma HCT-116 cells. In addition, neomarinone

generated a mean IC50 value of 10 M in the NCIs 60 cancer cell
line panel (Hardt et al. 2000; Kalaitzis et al. 2003).
Two new cytotoxic antibiotics, piericidins C7 and C8 (41) (Fig. 9),
were isolated from a marine Streptomyces sp. (Hayakawa et al.
2007a). Biological activity of piericidins was examined using rat
glial cells transformed with the adenovirus E1A gene (RG-E1A-7),
Neuro-2a mouse neuroblastoma cells, C6 rat glioma cells and 3Y1
rat normal broblast. Adenovirus E1A gene product inactivated the
retinoblastoma tumor suppressor protein that plays an important
role in cell-cycle and apoptosis control in mammalian cells and is
inactivated during the development of a wide variety of cancers
(Morgenbesser et al. 1994). Piericidins C7 and C8 showed selective
cytotoxicity against RG-E1A-7 cells (IC50 of 1.5 nM and 0.45 nM,
respectively), and inhibited the growth of Neuro-2a cells (IC50 of
0.83 nM and 0.21 nM, respectively) without cytotoxic cell death.
On the other hand, C6 rat glioma cells and 3Y1 rat normal broblast
were not affected by piericidins (Hayakawa et al. 2007b).
Lucentamycins (42) (Fig. 9), 3-methyl-4-ethylideneprolinecontaining peptides, are produced by Nocardiopsis lucentensis strain
CNR-712, isolated from the sediments of a shallow saline pond from
the island of Little San Salvador, in the Bahamas. Lucentamycins A
and B showed signicant in vitro cytotoxicity against human colon
carcinoma HCT-116 cell line with IC50 values of 0.20 and 11 M,
respectively. However, lucentamycins C and D were not cytotoxic
in the same assay, suggesting that the presence of an aromatic ring
is essential for the biological activity of this class of compounds
(Cho et al. 2007).
The new cyclohexadepsipeptides, arenamides A (43) (Fig. 9),
were isolated from the fermentation broth of a marine actinobacterial strain identied as S. arenicola CNT-088 which was obtained
from the marine sediments at a depth of 20 m off the Great Astrolab
Reef, in the Kandavu Island chain, Fiji. Arenamides A and B exhibited

weak in vitro cytotoxicity against human colon carcinoma HCT-116
with IC50 values of 13.2 and 19.2 g/mL, respectively (Asolkar et al.
2008). In addition, arenamides have been associated to chemoprevention of carcinogenesis by suppression of NFB activation. NFB
regulates the expression of a number of genes, the products of
which are involved in tumorigenesis (Aggarwal et al. 2006; Melisi
and Chiao 2007). Effect of arenamides on NFB activity was studied
with stably transfected 293/NFB-Luc human embryonic kidney
cells, induced by treatment with tumor necrosis factor (TNF). Arenamides A and B blocked TNF-induced activation in a dose- and
time dependent manner with IC50 values of 3.7 and 1.7 M, respectively (Asolkar et al. 2008).
Piperazimycins (44) (Fig. 10) are cyclic hexadepsipeptides isolated from the fermentation broth of a Streptomyces sp. strain
CNQ-593, isolated from marine sediments at a depth of approximately 20 m near the island of Guam. Cytotoxic activities of
piperazimycins were initially evaluated in vitro against the human
colon carcinoma HCT-116 cell line. All compounds exhibited signicant cytotoxicity with an average GI50 of 76 ng/mL for each.
Piperazimycin A also showed potent biological activity when evaluated against the NCIs cancer cell line panel, with mean GI50 ,
TGI and LC50 values for all the cell lines of 100 nM, 300 nM and
2 M, respectively. Overall, piperazimycin A exhibited a nearly 3fold more potent activity against solid tumors (average LC50 of
13.9 M) than against the leukemia cell lines tested (average LC50 of
31.4 M). It was most active against the melanoma (average LC50
of 0.3 M), central nervous system (average LC50 of 0.4 M) and
prostate cell lines (average LC50 of 0.6 M) cancers (Miller et al.
2007). Mansouramycin C (45) (Fig. 10) is an isoquinolinequinones
antibiotic isolated from Streptomyces sp. Cytotoxicity proling of
the mansouramycins in a panel of up to 36 tumor cell lines indicated
272
Fig. 9. Chemical structure of Piericidin, Lucentamycin A, Lucentamycin B, Lucentamycin C, Lucentamycin D and Arenamides A.
signicant cytotoxicity of several derivatives, with pronounced

selectivity for non-small cell lung cancer, breast cancer, melanoma
and prostate cancer cells (Hawas et al. 2009).
Usabamycins (46) (Fig. 10) are new anthramycin-type analogs
isolated from Streptomyces sp. NPS853. Usabamycins show weak
inhibition of HeLa cell growth and selective inhibition of serotonin
(5-hydroxytrypamine) 5-HT2B uptake (Sato et al. 2011). Pyridinium
(47) (Fig. 10) is an antibiotic isolated from Amycolatopsis alba.
The compound showed potent cytotoxic activity against cancer
cell lines of cervix (HeLa), breast (MCF-7) and brain (U87MG)
in vitro and also exhibited antibacterial activity against Grampositive and Gram-negative bacteria (Dasari et al. 2012). This new
-pyrone containing secondary metabolite was detected by HPLCDAD analysis in a culture ltrate extract of Streptomyces sp. NTK
227, a strain isolated from the Atlantic Ocean. Albidopyrone (48)

(Fig. 10) showed moderate inhibitory activity against proteintyrosine phosphatase B (Hohmann et al. 2009b).
3.6. Cytostatic activity
Proximicins are aminofuran antibiotics, probably synthesized
by a NRPS system, produced by Verrucosispora strain MG-37 and
Verrucosispora maris AB-18-032, and isolated from sediments collected at a depth of 250 m in the Raune Fjord, Norway and the
Sea of Japan at a depth of 289 m, respectively (Riedlinger et al.
2004; Fiedler et al. 2008). The characteristic structural element of
proximicins is 4-amino-furan-2-carboxylic acid, hitherto unknown
c-amino acid (Schneider et al. 2008). Proximicins A (49), B (50)
Fig. 10. Chemical structure of Piperazimycin, Mansouramycin C, Usabamycins, Pyridinium and Albidopyrone.
273
Fig. 11. Chemical structure of Proximicins A, Proximicins B, Proximicins C and Cyclomarin A.
and C (51) (Fig. 11) exhibit weak antibacterial activity but have
a strong cytostatic effect against various human tumor cell lines.
Proximicins A, B and C showed signicant growth inhibitory activity against human gastric adenocarcinoma AGS (GI50 of 0.6, 1.5
and 0.25 M, respectively) and hepatocellular carcinoma Hep G2
(GI50 of 0.82, 9.5 and 0.78 M, respectively) (Fiedler et al. 2008;
Schneider et al. 2008), and were found to induce the arrest of AGS
cells in G0/G1 and to increase the levels of p53 and p21 (Schneider
et al. 2008).
3.7. Anti-inammatory activity

Infectious disease is the number one cause of death in tropical countries accounting for approximately half of all fatalities.
In addition, infectious disease mortality rates are also increasing in developed countries (Pinner et al. 1996). Emerging and
re-emerging infections are thought to be driven largely by socioeconomic, environmental and ecological factors (Daszak et al. 2000;
Morens et al. 2004; Woolhouse 2008). Jones et al. (2008) reported
the emergence of 335 infectious diseases between 1940 and 2004 in
the global human population. These negative health trends call for a
renewed interest in infectious disease as well as effective strategies
for treatment and prevention. With respect to the development of
new antimicrobials, the marine environment holds great promise
for the discovery of novel bioactive compounds.
Abdelmohsen et al. (2010) isolated 90 actinomycetes from 11
different species of marine sponges. Testing for anti-infective activities was performed against clinically relevant, Gram-positive (E.
faecalis, S. aureus) and Gram-negative (Escherichia coli, Pseudomonas
aeruginosa) bacteria, fungi (C. albicans) and human parasites (Leishmania major, Trypanosoma brucei). It showed a high diversity of
actinomycetes associated with marine sponges as well as highlight their potential to produce anti-infective agents (Abdelmohsen
et al. 2010). Cyclomarin A (52) (Fig. 11) is a new cyclic heptapeptides antibiotic isolated from Streptomyces sp. It displayed
signicant anti-inammatory activity in both in vivo and in vitro
assays (Renner et al. 1999). Salinamides A and B (53) (Fig. 12) are
bicyclic depsipeptides, produced by Streptomyces sp. CNB-091, isolated from the jelly sh Cassiopeia xamachana. These metabolites
are useful as antibiotic and anti-inammatory agents (Moore et al.
1999).
3.8. Anti-parasitic activity

Parasitic trypanosomatids cause a number of important diseases, including Chagas disease and the leishmaniasis (Lopes et al.
2011). Chagas disease is a potentially life-threatening illness caused
by the agellate protozoan Trypanosoma cruzi. An estimated 10 million people are infected worldwide, mostly in Latin America where
Chagas disease is endemic. More than 25 million people are at risk
of the disease. It is estimated that in 2008 Chagas disease has killed
more than 10,000 people. Unfortunately, there is no ideal treatment
for the infection, especially for the chronic phase. In Brazil, only
benznidazole is available for the treatment of the disease, although
this drug presents toxic side effects and is active only in the acute
phase of illness (Urbina and Docampo 2003).
Leishmaniasis is a neglected tropical disease caused by parasitic protozoa of the genus Leishmania and threatens 350 million
people in 88 countries around the world. There are several different forms of leishmaniasis. The most common are cutaneous and
visceral. The causative Leishmania species of cutaneous leishmaniasis are Leishmania amazonensis, L. major, L. tropica, Leishmania
ethiopica, Leishmania braziliensis, and Leishmania mexicana, Leishmania donovani and Leishmania infantum are the main etiologic
agents of visceral leishmaniasis (Croft and Coombs 2003). Administration of pentavalent antimony organic compounds remains
as the rst choice therapy for leishmaniasis forms, followed by
amphotericin B, pentamidine and miltefosine. However, all currently available chemotherapeutic agents have serious drawbacks,
like severe side effects and parenteral administration for long time
(Croft and Coombs 2003; Shukla et al. 2010). In this unfavorable
scenario the development of new drugs for the treatment of Chagas
disease and leishmaniasis is mandatory.
Anti-parasitics are a class of medications which are indicated
for the treatment of parasitic diseases caused by L. major and
T. brucei that cause leishmaniasis and African sleeping sickness,
respectively. Alarming death rate caused by these parasites and
the emergence of antibiotic resistance underline the need for new
and effective drugs. Pimentel-Elardo et al. (2010) isolated Streptomyces sp. from Mediterranean sponges, studied their secondary
metabolite production and screened for anti-infective activities.
Bioassay-guided isolation and purication yielded three previously
known compounds namely, cyclic depsipeptide valinomycin,
indolocarbazole alkaloid staurosporine and butenolide. These
274
Fig. 12. Chemical structure of Salinamides, Avermectin, Trioxacarcin and Benzastatin C.
compounds exhibited novel anti-parasitic activities specically

against L. major (valinomycin IC50 < 0.11 M; staurosporine
IC50 5.30 M) and T. brucei brucei (valinomycin IC50 0.0032 M;
staurosporine IC50 0.022 M; butenolide IC50 31.77 M) (PimentelElardo et al. 2010). Avermectins (54) (Fig. 12) are a complex of
chemically related agents which exhibit extraordinarily potent
anti-parasitic activity. They are produced by a novel species of actinobacterium, NRRL 8165, Streptomyces avermitilis. The avermectin
complex is fully active against the gastrointestinal nematode
Nematospiroides dubius when fed to the infected mice for 6 days at
0.0002% of the diet (Burg et al. 1979).
3.9. Anti-malarial activity
Malaria is caused by intraerythrocytic protozoan parasites of
the genus Plasmodium. It is responsible for more than 300 million
clinical cases and over 2 million deaths annually. P. falciparum that
causes the most lethal form of the disease, is becoming increasingly resistant to almost all available drugs in the anti-malarial
armamentarium. New chemotherapeutic strategies are therefore
urgently needed to combat this disease (Reynolds et al. 2007).
Trioxacarcins are complex compounds showing higher antimalarial activity against the malarial pathogens and some of them
possess high antitumor and antibacterial activities. Trioxacarcin A,
B and C (55) (Fig. 12) were obtained from Streptomyces ochraceus
and Streptomyces bottropensis (Maskey et al. 2004b). Some of these
compounds possess extremely high antiplasmodial activity, which
is comparable to that shown by artemisinin, the most active compound against the pathogen of malaria.
3.10. Antiviral activity
Marine antiviral agents represent a signicantly unique natural
marine resource whose multi-potential uses include the following
applications: (1) biological control of human enteropathogenic
virus contamination and disease transmission in sewage-polluted
waters. This application would be particularly important to
communities that utilize the coastal waters for recreational activities and for food industries (e.g. sh, shellsh), as well as to those
regions of the country, such as Hawaii, where the loss of these
marine resources would have a devastating effect on the lifestyle
and economy of the people and (2) chemotherapy of viral diseases
of humans and lower animals.
To be of practical use, it is imperative that marine antiviral
agents are to be isolated from pure cultures, identied and characterized. Their spectrum and mechanism of antiviral activity should
also be clearly established. Their active principle(s) and moieties
should be identied and chemically characterized in order to facilitate application of biotechnological methods for increased yields
and cost effective production.
Currently, it appears that there have been only a few compounds
derived from marine actinobacteria with antiviral activity. Benzastatin C (56) (Fig. 12), a 3-chloro-tetrahydroquinolone alkaloid
obtained from Streptomyces nitrosporeus, showed antiviral activity in a dose-dependant manner with EC50 values of 1.92, 0.53,
and 1.99 g/mL against herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2) and vesicular stomatitis virus
(VSV), respectively (Lee et al. 2007). Kumar et al. (2006) reported
the antiviral property of a marine Streptomyces against White Spot
Syndrome Virus (WSSV) in penaeid shrimps. WSSV infection can
cause cumulative mortality up to 100% within 310 days, thereby
causing considerable economic loss to the shrimp farmers. In this
context, antibiotic extracts were obtained from the fermentation
broth of twenty-ve isolates of marine Streptomyces (isolated from
the coastal waters of Southwest coast of India), incorporated into
the formulated feeds and supplemented to the post-larvae (PL-20)
of the black tiger shrimp Penaeus monodon for 2 weeks and challenged with WSSV. The pattern of post-challenge survival % (PCS %)
in the 27 treatments (25 experimental and two controls) exhibited
a wide range of variation from 11 to 83% during the course of the
experiment. PCS % was lowest in the controls (C1-4.3%, C2-5.2%) on
day 7. However, six probiotic feeds (SA 2, SA 8, SL 27, SL 33, SL 39,
and SL 85) supplemented to postlarval shrimp recorded the highest
PCS %, ranging between 50 and 83%. Also, severity of the infection
275
Fig. 13. Chemical structure of Dermacozines, Lipocarbazoles, Streptopyrrolidine and Cyclo-(l-Pro-l-Met).
observed on days 35 in post-larval shrimp fed with other diets,

was not visible in these groups. In this case, positive effect was
obtained by the antibiotic extract incorporated in the feed against
WSSV infected penaeid shrimps (Kumar et al. 2006).
in accordance with their chemical structure, exhibited strong free

radical scavenging activity (Schneider et al. 2009).
3.12. Anti-angiogenesis activity

3.11. Antioxidant activity
Antioxidant means against oxidant. An antioxidant is any
substance that retards or prevents deterioration, damage or
destruction by oxidation (Dekkers et al. 1996). It is a classication
of several organic substances, including vitamins C and E, vitamin
A, selenium and a group known as the carotenoids (Dekkers et al.
1996; Kaczmarski et al. 1999).
Dermacozines A-G (57) (Fig. 13) are new the oxidized and
reduced phenazine-type pigments of Dermacoccus isolated from
the sediments of the Challenger Deep (10898 m) of the Mariana
Trench (Pathom-Aree et al. 2006b). HPLC-DAD analysis of culture ltrates of these isolates showed an interesting pattern of
secondary metabolites, a group of phenazine compounds. Highresolution mass spectrometry and structural eludication of these
compounds resulted in the identication of 14 novel phenazinetype metabolites which were named dermacozines. Structures
of seven of these compounds, showing free radical scavenging
activities and antitumor and antiprotozoal activities have been
determined. Dermacozines F and G exhibited moderate cytotoxic
activity against leukemia cell line K562 with IC50 values of 9 and
7 M, respectively while the highest radical scavenger activity was
observed in dermacozine C with an IC50 value of 8.4 M (AbdelMageed et al. 2010).
A family of new secondary metabolites with a carbazole moiety
and an alkyl side chain were detected by HPLC-DAD analysis in
the cell extracts of Tsukamurella pseudospumae strain Acta 1857.
Metabolites, which were named as lipocarbazoles (58) (Fig. 13),
Angiogenesis is an essential step in tumor cells proliferation,

development, and metastasis (Risau 1997). It is generally accepted
that there are two stages of tumor progression regarding its vasculature (Reynolds et al. 1992; Folkman 1995). In initial vascular stage
of tumor growth (tumor mass < 0.5 mm), it receives nutrition and
oxygen from blood by diffusion. When tumor mass grows larger
than 0.5 mm, nutrition through diffusion is not sufcient for further growth (vascular stage) and therefore, the formation of new
blood vessels (angiogenesis) is necessary to draw nutrition directly
from the systemic circulation (Folkman 1990). The tumor remains
in a dormant state until it can stimulate blood vessel growth from
nearby pre-existing capillaries (Weidner et al. 1993). Inhibiting
angiogenesis has been considered as an important anticancer strategy to suppress tumor growth and metastasis.
As the marine environmental conditions are extremely different
from that of the terrestrial ones, marine microbes have different characteristics and therefore, might produce different types of
bioactive compounds in their challenging living conditions (Lam
2006). Streptopyrrolidine (59) (Fig. 13) is a benzyl tetrahydropyrrole derivative produced by Streptomyces sp. KORDI-3973 isolated
from the deep-sea sediments at Ayu Trough, in the southern Philippine Sea. Streptopyrrolidine showed anti-angiogenesis activity on
human umbilical vein endothelial cells (HUVECs) based capillary
tube formation assay. The inhibition of tube formation was exerted
without showing cytotoxicity against HUVECs at the concentration
of 100 g/mL (Shin et al. 2008). Cyclo-(l-Pro-l-Met) (60) (Fig. 13)
was isolated from the fermentation broth of a marine-derived actinomycete Nocardiopsis sp. 03N67 by chromatographic analysis and
276
it showed anti-angiogenesis activity against human umbilical vein

endothelial cells (HUVECs) (Shin et al. 2010).
4. Conclusion and future perspectives
Substantial increases in the interest pertaining to natural products, especially those originating from marine organisms, and
proven potential of marine actinobacteria to synthesize diverse
compounds have brought marine actinobacteria into the focus
of intensive research. It seems likely that two major parallel
approaches will be developed for drug discovery from marine actinobacteria. One will be based on establishment of new and further
development of existing isolation and cultivation techniques, to
increase the diversity of cultivable isolates, shorten the time of
cultivation to achieve appreciable cell mass for higher yields and
production of secondary metabolites. As the actinobacteria are
very diverse and each species might have special requirements not
only for growth, but also for the production of secondary metabolites, this approach will require considerable novel and innovative
efforts. Its major advantage is that, if successful, it will result in the
production of a compound whose structure, novelty and biological
activity can be assessed straight away.
As the cultivation-dependent technology is unlikely to reveal
the full biosynthetic potential, the second approach, genome-based
bioprospecting, has to be undertaken in order to address this question. Its success will depend on factors such as development of
efcient tools for bioinformatic analysis of the genomes allowing
identication of unique biosynthetic gene clusters, chemoinformatic software for prediction of structural features based on gene
analysis and further development of host/vector systems for heterologous expression of gene clusters. Strong interplay of classical
natural product chemistry with modern microbial genetics and
bioinformatics will denitely help overcome the supply and sustainability issues of the past and to promote the production of
bioactive substances from marine actinobacteria as a well recognized alternative for future drug discovery programs.
Acknowledgments
This research was supported by a grant from Marine Bioprocess Research Center of the Marine Biotechnology Program funded
by the Ministry of Oceans and Fisheries, Republic of Korea. One of
the authors Kannan Sivakumar expresses his thanks to the Director, Centre of Advanced Study in Marine Biology, Faculty of Marine
Sciences and Annamalai University authorities for facilities and
encouragement.
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Microbiological Research 169 (2014) 262278

Contents lists available at ScienceDirect

Pharmaceutically active secondary metabolites of marine

This article is part of a Special Issue entitled Medicinal Extracts in Microbiology.

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

Conclusion and future perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276

molecules. It has an enormous biosynthetic potential that remains

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

Riedlinger et al. (2004)

Maskey et al. (2003b)

Feling et al. (2003)

Chauhan et al. (2005)

Bruntner et al. (2005)

Gao et al. (2012)

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

Schneider et al. (2008)

Renner et al. (1999)

Burg et al. (1979)

Maskey et al. (2004b)

Lee et al. (2007)

Abdel-Mageed et al. (2010)

Shin et al. (2008)

3. Secondary metabolites from marine actinobacteria

Schneider et al. (2009)

BD21-2, obtained from a shallow-water sediment sample collected

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

structure. Caboxamycin showed inhibitory activity against both

antibacterial activity (Macherla et al. 2005). Tirandamycin C (15)

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

respectively, and was determined to be bactericidal by time-kill

produced the enzyme chitinase and showed antifungal activities

Fig. 3. Chemical structure of Lynamicins, Marinopyrroles, Caboxamycin, Himalomycin A and Himalomycin B.

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

sorokiniana and antibacterial activity against S. aureus and Bacillus

individually useful in particular situations and when combined,

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

2005). However, number of these new antibiotics is noted to have

Fig. 6. Chemical structure of Mechercharmycin A, Arenicolide, Chalcomycin and Daryamide A.

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

Chalcomycin (26) (Fig. 6), a 16-membered macrolide, is produced

Palau island, Western Pacic Ocean. Biological activity of these

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

human colon carcinoma HCT-116 cells. In addition, neomarinone

Reef, in the Kandavu Island chain, Fiji. Arenamides A and B exhibited

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

signicant cytotoxicity of several derivatives, with pronounced

227, a strain isolated from the Atlantic Ocean. Albidopyrone (48)

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

Fig. 11. Chemical structure of Proximicins A, Proximicins B, Proximicins C and Cyclomarin A.

3.7. Anti-inammatory activity

3.8. Anti-parasitic activity

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

Fig. 12. Chemical structure of Salinamides, Avermectin, Trioxacarcin and Benzastatin C.

compounds exhibited novel anti-parasitic activities specically

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

Fig. 13. Chemical structure of Dermacozines, Lipocarbazoles, Streptopyrrolidine and Cyclo-(l-Pro-l-Met).

observed on days 35 in post-larval shrimp fed with other diets,

in accordance with their chemical structure, exhibited strong free

3.12. Anti-angiogenesis activity

Angiogenesis is an essential step in tumor cells proliferation,

P. Manivasagan et al. / Microbiological Research 169 (2014) 262278

it showed anti-angiogenesis activity against human umbilical vein