Marine Drugs: Implication and Future Studies
R. Arthur James
Natural product compounds are the source of numerous therapeutic agents. Recent progress to discover drugs from natural product sources has resulted in compounds that are being developed to treat cancer, resistant bacteria and viruses and immunosuppressive disorders. Many of these compounds were discovered by applying recent advances in understanding the genetics of secondary metabolism in microorganisms, exploring the marine environment and applying new screening technologies. Microbes have made a phenomenal/unique contribution to the health and well-being of people throughout the world. In addition to producing many primary metabolites, such as amino acids, vitamins and nucleotides, they are capable of making secondary metabolites, which constitute half of the pharmaceuticals on the market today (and provide agriculture with many essential products). A growing number of marine microorganisms are the sources of novel and potentially life-saving bioactive secondary metabolites. Here, we have discussed some of these novel antibacterial, antiviral, anticancer compounds isolated from marine-derived microbes and their possible roles in disease eradication and commercial exploitation of these compounds for possible drug development using many approaches.
September 03, 2010; Accepted: September 24, 2010;
Published: November 16, 2010
The oceans cover over 70% of the earth's surface and contain an extraordinary
diversity of life. Our interest in understanding the function of marine ecosystems
has been accelerated in recent years with growing recognition of their importance
in human life. Marine microbes have defined the chemistry of the oceans and
atmosphere over evolutionary time. Thousands of different species of bacteria,
fungi and viruses exist in marine ecosystems comprising complex microbial food
webs. These microorganisms play highly diverse roles in terms of ecology and
biochemistry, in the most different ecosystems and each drop of water taken
from the ocean will contain microbial species unknown to humans in a 9:1 ratio
(Colwell, 2002). The ocean represents a rich resource
for ever more novel compounds with great potential as pharmaceutical, nutritional
supplements, cosmetics, agrichemicals and enzymes, where each of these marine
bioproducts has a strong potential market value (Faulkner,
2002). A lot of structurally and pharmacologically important substances
have been isolated with novel antimicrobial, antitumor and anti-inflammatory
properties (Bhadury and Wright, 2004). In many cases,
natural products provide compounds as clinical/marketed drugs, or as biochemical
tools that demonstrate the role of specific pathways in disease and the potential
of finding drugs. In the areas of cancer and infectious disease, 60 and 75%,
respectively, of new drugs, originate from natural sources. Raja
et al. (2010) reported that new antibiotics active against resistant
bacteria are required. Bacteria live on earth for several billion years. During
this time, they encountered by range of naturally occurring antibiotics. To
survive, bacteria developed antibiotics resistance mechanism (Hoskeri
et al., 2010).
Natural products with industrial/human applications can be produced from primary
or secondary metabolism of living organisms such as microorganisms. Among, them
50-60% are produced by plants (alkaloids, flavonoids, terpenoids, steroids,
carbohydrates, etc.) and 5% have a microbial origin. Furthermore, from the 22,500
biologically active compounds that has been obtained so far from microbes, 45%
are produced by actinomycetes, 38% by fungi and 17% by unicellular bacteria
(Berdy, 2005). The increasing role of microorganisms
in the production of antibiotics and other drugs for treatment of serious diseases
has been dramatic. However, the development of resistance in microbes and tumor
cells has become a major problem and requires much research effort to combat
Several reviews explore the development of marine compounds as drugs. There
have been reviews on aspects of the chemistry and bioactivity of compounds from
microbes, soft corals, cyanobacteria and microalgae, cyanobacteria and macroalgae,
sponges, echinoderms, ascidians, fish, the sponge genus Halichondria,
terpenes from the soft coral genus Sinularia and specific types of bioactivity
associated with marine natural products have been reviewed in articles on anticancer
drugs, agents for treating tuberculosis, malaria, osteoporosis and Alzheimers
disease, treatments for neurological disorders, anti-inflammatory agents anti
anti-HIV compounds (Blunt et al., 2007).
Secondary metabolites, especially drugs have exerted a major impact on the
control of infectious diseases and other medical conditions and the development
of pharmaceutical industry. Their use has contributed to an increase in the
average life expectancy in the USA, which increased from 47 years in 1900 to
74 years (in men) and 80 years (in women) in 2000 (Lederberg,
2000). As a great promising source for new natural products which have not
been observed from terrestrial microorganisms, marine bacteria are being developed
for the discovery of bioactive substances with new types of structure, with
growing intensive interest. The achievements have been well reviewed, where
many new antibiotics were obtained from microorganisms. With drug resistant
strains of microbes appearing more frequently the biopharmaceutical industry
has to move towards novel molecules in their development of new drugs. The oceans
provide us with an opportunity to discover many new compounds, with over 13,000
molecules described already and 3,000 of them having active properties. Marine
organisms have long been recognized as a source of novel metabolites with applications
in human disease therapy.
HISTORY OF ANTIBIOTIC
Back in 1928, Alexander Fleming1 began the microbial drug an era. When, he
discovered in a Petri dish seeded with Staphylococcus aureus that a compound
produced by a mold killed the bacteria. The mold, identified as Penicillium
notatum, produced an active agent that was named Penicillin. Later,
penicillin was isolated as a yellow powder and used as a potent antibacterial
compound during World War II. By using Flemings method, other naturally
occurring substances, such as chloramphenicol and streptomycin, were isolated.
Naturally occurring antibiotics are produced by fermentation, an old technique
that can be traced back almost 8000 years, initially for beverages and food
production (Balaban and DellAcqua, 2005).
REASONS FOR DEVELOPING NEW ANTIBIOTICS FROM MARINE SOURCES
The WHO has predicted that between 2000 and 2020, nearly 1 billion people will
become infected with Mycobacterium tuberculosis (TB). Sexually transmitted
diseases have also increased during these decades, especially in young people
(aged 15-24 years). HIV/AIDS has infected more than 40 million people in the
world. Together with other diseases such as tuberculosis and malaria, HIV/AIDS
accounts for over 300 million illnesses and more than 5 million deaths each
year. Additional evolving pathogens include the Ebola virus, which causes the
viral hemorrhagic fever syndrome with a resultant mortality rate of 88%. It
is estimated that this bacterium causes infection in more than 70,000 patients
a year in the USA (Balaban and DellAcqua, 2005).
The Infectious Disease Society of America (IDSA) reported in 2004 that in US
hospitals alone, around 2 million people acquire bacterial infections each year
Staphylococcus aureus is responsible for half of the hospital-associated
infections and takes the lives of approximately 100, 000 patients each year
in the USA alone (Hancock, 2007). New antibiotics that
are active against resistant bacteria are required. The problem is not just
antibiotic resistance but also multidrug resistance. In 2004, more than 70%
of pathogenic bacteria were estimated to be resistant to at least one of the
currently available antibiotics (Cragg and Newman, 2001).
Among them, Pseudomonas aeruginosa accounts for almost 80% of these
opportunistic infections. They represent a serious problem in patients hospitalized
with cancer, cystic fibrosis and burns, causing death in 50% of cases. Other
infections caused by Pseudomonas species include endocarditis, pneumonia
and infections of the urinary tract, central nervous system, wounds, eyes, ears,
skin and musculoskeletal system. This bacterium is another example of a natural
multi drug-resistant microorganism (Balaban and DellAcqua,
2005). Several viruses responsible for human epidemics have made a transition
from animal host to humans and are now transmitted from human to human. In addition,
the major viral causes of respiratory infections include respiratory syncytial
virus, human parainfluenza viruses 1 and 3, influenza viruses A and B, as well
as some adenoviruses. These diseases are highly destructive in economic and
social as well as in human terms and cause approximately 17 million deaths year-1
and innumerable serious illnesses besides affecting the economic growth, development
and prosperity of human societies (Morse, 1997).
METABOLITES FROM MARINE MICROORGANISMS
Marine organisms comprise approximately half of the total biodiversity on the
earth and the marine ecosystem is the greatest source to discover useful therapeutics.
Sessile marine invertebrates such as sponges, bryozoans, tunicates, mostly lacking
morphological defense structures have developed the largest number of marine-derived
secondary metabolites including some of the most interesting drug candidates.
|| Potential antimicrobial/anticancer compounds from marine
In recent years, a significant number of novel metabolites with potent pharmacological
properties have been discovered from the marine organisms.
Although, there are only few marine-derived products currently in the market,
several marine natural products are now in the clinical pipeline, with more
undergoing development (Rawat et al., 2006).
Similar work has been conducted targeting uncultivable microbes of marine sediments
and sponges using metagenomic-based techniques to develop recombinant secondary
metabolites (Moreira et al., 2004). Marine bacteria
are emerging as an exciting resource for the discovery of new classes of therapeutics.
The promising anticancer clinical candidates like salinosporamide A and bryostatin
only hint at the incredible wealth of drug leads hidden just beneath the ocean
surface. Salinosporamide A, which is isolated from marine bacteria that is currently
in several phase I clinical trials for the treatment of drug-resistant multiple
myelomas and three other types of cancers (Ahn et al.,
Microbes generally lack an active means of defense and thus have resulted in developing chemical warfare to protect them from attack. In addition, many invertebrates (including sponges, tunicates, bivalves, etc.) are filter feeders, resulting in high concentrations of marine viruses and bacteria in their systems. For their survival, potent antiviral and antibacterials had to be developed to combat any opportunistic infectious organisms (Table 1). It is hoped that many of these chemicals can be used as the basis for future generations of antimicrobials usable in humans.
MARINE NATURAL PRODUCTS BEING THE NEW SOURCE OF LEAD COMPOUNDS
In the past natural products have been a strong source for novel drug products,
or have been a model for a drug that has made it to market (Cragg
et al., 2006). The reasons for the strong showing of drug discovery
from natural products can be attributed to the diverse structures, intricate
carbon skeletons and the ease that human bodies will accept these molecules
with minimal manipulation. The current trend within drug development is to find
new precursor molecules from synthetic molecules as it is more cost-effective.
This is because the techniques used with natural products include complex screening
procedures that are time-inefficient and expensive.
In addition, a biological response from the mixture containing the compound
may not be attributed to the chemical entity in question, but by another substance
within the extract interfering with the screening procedure. The modern pharmaceutical
shelves house a variety of compounds; however, there are a limited number of
products on store shelves that are derived from a marine source. Historically,
the first two compounds to make it to market from a marine source are Ara-A
(Vidarabine®, Vidarabin®, Thilo®) and Ara-C (Cytarabine, Alexan®,
Udicil®) (Patrzykat and Douglas, 2003). These compounds
were isolated by Bergmann and Feeney (1951) and are
still prescribed today. Ara-A is an anti-viral compound isolated from a sponge;
Ara-C is isolated from the same sponge (Cryptotethya crypta) and has anti-leukemic
properties. Natural products are becoming more popular again as marine organisms,
both multi- and single-cellular, are an excellent resource with which to find
novel chemical entities. Further, many chemical compounds isolated from marine
organisms have great potential as antimicrobials or cytotoxic compounds due
to the reliance of marine organisms on antimicrobial compounds or cytotoxic
molecules as their innate defense mechanisms (Fig. 1a-e).
There are currently over 3000 new substances identified from marine organisms
in the past three decades, giving researchers a large pool of novel molecules
from which to find new compounds to develop (Florida Atlantic University, http://www.science.fau.edu/drugs.htm).
||Chemical structure of metabolites from marine sources. (a)
convalutamines-bryozoans non-halogenated SesQuiterpene molluscs, (b) 3-heptacosoxypropane-1,2-diol
sponges, (c) kalkitoxin-cyanobacteria, (d) lornemides A-actinomycetes aigialomycin
D-fungi and (e) IB-96212-bacteria
For example, if properly developed, marine bacteria could provide the drugs
needed to sustain us for the next 100 years in our battle against drug-resistant
infectious diseases. Over the past century, the therapeutic use of bacterial
natural products such as actinomycin D, daunorubicin, mitomycin, tetracycline
and vancomycin has had a profound impact on human health, saving millions of
lives. In the past 10 years (1997-2008), 659 marine bacterial compounds have
been described. Marine fungi have proved to be a rich source of bioactive natural
products. Most of these micro-organisms grow in a unique and extreme habitat
and therefore they have the capability to produce unique and unusual secondary
metabolites. To date, more than 272 new compounds have been isolated from the
marine fungi and the number of compounds is on the increase (Tziveleka
et al., 2003). According to the World Health Organization 100 million
of people in the developing countries are affected by infectious diseases (Lee
et al., 2009).
NEW DRUG FROM ENGINEERED MICROORGANISMS
Many chemicals and biological molecules that have been used as drugs are found in microorganisms, plants and animals. As these drugs are synthesized in only minute amounts, it is difficult to obtain them in suitable amounts. This is where metabolic engineering comes into play. The sequencing of genomes from cultivable microorganisms, chromosomal DNA is used to generate genomic libraries. Large genomic DNA fragments are directly isolated from the sample and cloned into suitable host vector systems (Fig. 2). Establishment of comprehensive gene libraries attempts to cover all genome sequences from sample, to gather as much information as possible on the biosynthetic machinery of a microflora.
Recent advances in our understanding on the metabolic pathways for the synthesis
of these drugs together with the development of various genetic and analytical
tools have enabled more systematic and rigorous engineering of microorganisms
for enhanced drug production. Much rapid growth of microbial cells compared
with higher organisms is another obvious advantage. Furthermore, metabolic engineering
of microorganisms can be performed more easily than mammalian and plant cells,
which allows modification of metabolic pathways for the production of structurally
more diverse analogs with potent biological activities, as in the cases of polyketides
and non-ribosomal peptides (Minami et al., 2008).
||Common schematic representation of rDNA (recombinant DNA)
preparation from Marine environmental (Microorganisms) samples (Thakur
et al., 2008)
Although production of drugs at their final forms may be most desirable, biosynthesis
of drug precursors is also favored experimentally and economically in several
cases. High impact of microbial metabolic engineering toward the biosynthesis
of drug precursors is well illustrated by the recent development of microbial
Various drug molecules can be produced by employing metabolically engineered
S. cerevisiae with appropriate heterologous genes using the same precursor
synthesized by engineered E. coli. This is a good example of what metabolic
engineering can do for the design and production of drug precursors that are
difficult to obtain otherwise Biosynthetic capacity of marine Verrucosispora
and Salinospora strains demonstrate that marine actinomycetes represent a new
and potent source of bioactive secondary metabolites (De
Vries and Beart, 1995). Shizuya et al. (1992)
developed the bacterial cloning system Bacterial Artificial Chromosome (BAC)
for mapping and analysis of complex genomes. Because of its high cloning efficiency
and the stable maintenance of inserted DNA, the BAC system is able to facilitate
the construction of DNA libraries of complex genomic samples but also provides
a comprehensive representation of genome sequence of one organism. The ability
to clone long stretches of DNA has become an important tool for genome analyses
of uncultivated marine microorganisms (Fig. 3).
We may be able to incorporate the genes that produce the molecules scientists are interested in within plasmids of bacteria that we can easily grow. Drug production by metabolically engineered microorganisms has several advantages over total chemical synthesis or extraction from natural resources.
IDENTIFICATION OF NEW ANTIMICROBIAL COMPOUNDS
Most of the antimicrobial compounds currently on the market were screened based on whole cell antimicrobial screening programs. By application of new genome-driven techniques more directed, target-based approaches are possible. These new screening strategies are directly coupled to potential drug targets, which have been identified by genome sequencing projects. Such antimicrobial targets are for example proteins that are essential for microbial growth or cell survival. The sequencing of the genome of a microorganism that has been identified as a potent producer of bioactive compounds allows the identification of the gene clusters involved in the pathways for the production of these natural compounds (Fig. 4).
SCREENING FOR NEW METABOLITES
The screening results depend on the quality of screening material, collection
and storage of organisms, cultivation, extraction, storage of extracts and preparation
of test samples. A directed (preselected) screening offers better chances of
finding interesting metabolites than an undirected (blind) screening. Such a
directed screening could be based on ecological observations on traditional
experiences or search in novel organisms. Mode and solvent of extraction determine
which substances are extracted. Solid phase extraction is a suitable method
for automated sample preparation (Schmid et al.,
1999). Chemical and physicochemical screening is the search for new chemical
structures regardless of their biological activities. The chemical reactivity
or physicochemical properties of the separated compounds are analyzed by spectroscopic
methods (UV/VIS, MS, NMR) or by detection with special detection reagents in
the TLC. The development of HPLC-DAD-MS systems allows the specific detection
of single components in a complex mixture (e.g., an extract), regardless of
the background of other metabolites. During biological screening test samples
(extracts, fractions, pure compounds and compound libraries) are screened for
their bioactivities in vitro and/or in vivo. In the case of extracts,
active metabolites could be isolated by bioactivity-guided isolation processes.
The finding of structurally known compounds (dereplication) in active extracts
is possible. In vitro tests could be done on a molecular or on a cellular
level. An assay that requires careful interpretation but provides a lot of information
per assay is ideal for marine natural products research. Tests on the molecular
level are based, e.g., on receptor systems (identification of those compounds
which bind to one receptor) or on enzyme systems (enzyme-catalyzed turnover
Tests on the genome, transcriptome, or proteome level will become more and more important. Targets of high pharmacological relevance are G-protein coupled receptors, tyrosine kinase receptors, nuclear hormone receptors, ion channels, proteases, kinases, phosphatases and transporter molecules. The detection of a reaction on the molecular level could be done by biochemical assays (e.g., spectrophotometric measurement of the product of an enzymatic reaction), ligand binding assays (readout by labeling with a tracer) or functional assays (reporter gene assays quantifying the expression level of a specific reporter gene product, second messenger assays, two hybrid assays for measuring protein-protein interactions). Fluorescence-based assay technologies, isotopic labeling, colorimetry and chemoluminescence are very often used as detection methods. Cell-based assays are more complex and more physiologically relevant than tests on the molecular level. On the other hand, they are still labor intensive and more difficult to validate than molecular assays.
With the potential of so many new compounds to combat bacteria, viruses and
debilitating diseases such as alzheimers, osteoporosis and cancer why have marine
sources not been thoroughly investigated before? The disclosure of compound,
which organism it is isolated from and its structure become devalues leads to
pharmaceutical companies losing the advantages. Many marine organisms are found
in remote locations and can require large sums of money just to travel to and
from these locations. Additional expenses including the specialized services
of divers, submersibles and the personnels safety and costs can become
quite steep. An example of the prohibitive costs associated with collection
of marine organisms is that a ship and submersible costs $14,500 per day (Hale
et al., 2002).
FUTURE OF MARINE SOURCES
The future looks bright for the pharmaceutical industry to develop new drugs
from chemical structures isolated from marine sources. As of 2001 over 13,000
compounds, with 3000 of those denoted as being active compounds (those that
have exhibited potential pharmaceutical effects), have had their chemical structures
determined and documented (Fig. 5).
||Metabolites from marine microorganisms (Schweder
et al., 2005). (a) antitumor compound, (b) antibiotic compound,
(c) antiviral compound, (d) anti-inflammatory compound and (e) antifungal
The vast majority of these compounds are being developed in the hopes of treating
cancer, tumour growth and leukaemia-over 67% of compounds isolated from marine
origins have cytotoxic activity (Cragg et al., 2006).
Fifty years ago the search of drugs from marine sources was in its infancy and
even though progress has been slow pharmaceutical companies are beginning to
embrace the use of natural marine sources. In the research being conducted today,
we also see a future trend towards marine natural resources as the number of
papers reporting total syntheses or synthetic analogues are quite extensive.
Partial and formal syntheses of compounds with their origins from marine sources
are not documented in review in comparison, thus there are many more lead compounds
with their origins from marine natural sources than previously thought (Bourguet-Kondracki
and Kornprobst, 2005).
Investigators have a large amount of compounds to begin their investigations
with and will provide the basis for future generations of drug products (Table
2). Anticancer drugs derived from marine sources have not yet been approved
for market, yet a significant number are undergoing clinical trials and the
future appears to hold a cancer treatment based on a marine natural source.
Natural products have played a significant role in drug discovery. Over the past 75 years, natural product derived compounds have led to the discovery of many drugs to treat human disease. Drugs developed from marine sources give us this hope and also give us novel mechanisms to fight some of the most debilitating diseases encountered today, including: HIV, osteoporosis, Alzheimers disease and cancer. Although, the costs associated with developing drugs from marine sources have been prohibitive in the past, the development of new technology and a greater understanding of marine organisms and their ecosystem are allowing us to further develop our research into this area of drug development. This present review article will attempt to link these developments with some global issues and begin to present a convergent vision of many disparate views of the development of medicinal and biological agents from marine natural sources. This study is, in part, a commentary on finding a middle way, an as yet untrodden path in drug discovery, for the global health benefits of humankind from marine environment.
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