A. S. Ninawe, PhD
Director, Department of Biotechnology, Block II, CGO Complex
New Delhi, India
Marine organisms are a promising new source of bioactive substances.
For millennia, the plant kingdom has served as a fertile hunting ground for medicinal compounds, so it should come as no surprise that scientists are looking elsewhere in
the natural world for potential therapeutics. Specifically, they’re mining the seas to find microorganisms with chemically interesting and biologically significant secondary metabolites that might serve as lead compounds for potential drug development.
The ocean as a source
Initially, these efforts extended the search for pharmaceutical-yielding plants and focused mainly on metabolites from macroscopic marine algae and invertebrate animals—a search that gave rise to 3,700 products to date. But over the past decade, the search has widened to include marine microbes.
The ocean environment is massively complex, consisting of extreme variations in pressure, salinity, temperature, and biological habitats. To deal with the variety of ocean habitats, marine microorganisms have developed unique metabolic and physiological functions that not only ensure survival in extreme conditions, but also have given rise to diverse novel enzymes and bioactive metabolites to deal with those conditions. Some of these may also prove useful in therapeutic settings.
Indeed, the ocean provides a vast universe of untapped pharmaceutical potential. Only about one percent of marine animals have been examined for pharmacological activity, and only a few of those have been fully researched for their pharmacological properties.
The need for new therapeutic compounds has been expanding greatly because of the evolving resistance of microorganisms to existing antibiotics, the emergence of new viral diseases, and the appearance of drug-resistant tumors. Most antibiotics cannot be used in animals and humans because they are too toxic. Some toxic agents affect primarily rapidly dividing and growing cells and have been used by adjusting dosage and directing the action of these agents in treating various diseases. Several life-saving drugs have been developed from the extracted biochemicals of terrestrial plants, but similar work carried out on marine biota is relatively meager.
Preliminary results suggest that marine organisms may turn out to be a more important source of anticancer compounds than terrestrial plants. Didemin, isolated from the Caribbean tunicate,
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General scheme for extraction of bioactive compounds from marine organisms. (Source: Michael T. Morrissey, PhD, Oregon State University Seafood Lab)
Trideodemnum solidum, is active against leukemia and melanoma. It has also shown strong antiviral and immunosuppressive activity. Manolide, a secondary metabolite isolated from the South Pacific sponge, Luffariella variabilis, and a terpene with an unusual structure has anti-inflammatory and analgesic properties in addition to its antileukemic and antifungal properties. The sponges have proven to be a good source of secondary metabolites and several compounds have been isolated from them.
Most marine microorganisms are of the gram-negative eubacteria, cyanobacteria, and the myxobacteria groups, which are generally thought to produce many medically useful substances. Many microorganisms are capable of producing novel antibiotics. Istamycin, a new antibiotic, is produced by Streptomyces tenjimariensis, a bacterium isolated from the mud of a shallow bay in Japan. It appears to be an aminoglycoside that can inhibit a fairly large number of gram-positive and gram-negative bacteria. Aplasmomycins produced by Streptomyces griseus inhibit gram-positive bacteria and show an effective antimalarial activity. Flavobacterium ulginosum, isolated from the seaweed of Sugami bay in Japan, produces a substance named mariactin that inhibits the development of tumors in various animals by up to 95%. Extracts of marine Alteromonas rubre was observed to contain rubrenoic acid, which shows bronchodilator activity. This active metabolite purified from A. rubre was not one of the many known antibiotics produced by soil microorganisms. Other biological activities observed with the culture filtrates of Alteromonas sp. antiserotonin, anti-amphetamine, and hypotensives. Some aquatic fungal cell extracts show nicotinic blocker and polysynaptic activities.
Very few marine microorganisms are known to produce antiviral compounds. Products of the marine bacterium Vibrio marinus, inactivated enteroviruses, and Flavobacterium showed antiviral activity. Anti-poliovirus activity was detected with extracts of Pseudemonas and Vibrio.
Recently, studies have also suggested that some bioactive compounds isolated from marine invertebrates such as sponges, coelentrates, gorgonians, soft and hard corals, algae, mollusks, or protochordates originate from symbiotic microorganisms such as bacteria, fungi, blue green algae, dinoflagellates, or haptophytes. These compounds have been shown to exhibit antibiotic, antitumor, and other pharmacological activities. Derivatives of dictyotacean algae (Spatoglossum schmittii) spatol demonstrated toxicity against human melanoma and astrocytomat cells in culture. Stypopodium, a potent cytotoxin produced by Stypopodium zonale, appears to inhibit cancer cell damage. Thus, marine microorganisms represent important and untapped resources for novel bioactive compounds.
Useful products from invertebrates
Extracts from Green-lipped mussels found in waters off New Zealand were shown to have an anti-inflammatory effect useful in the treatment of arthritis. This extract has been used safely without any side effects. For example, at The Victoria Infirmary in Glasgow, 76% of patients with rheumatoid arthritis and 45% of those with osteoarthritis reported improvement with this extract.
In India, marine mollusks and clams were examined for the recovery of heparin, a common anticoagulant. Presently, heparin is prepared from animal tissues that are rich in mast cells, such as porcine intestinal mucosa and beef lung. Naturally occurring low molecular weight heparin may be harvested more cheaply from India’s abundant coastal waters.
Marine fish oil is a rich source of eicosapentoic acid (EPA) and docosahexaenoic acids (DHA), which are particularly useful in the treatment of various cardiovascular disorders. EPA and lectins from marine species have
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Novel bioactive compounds from ocean. (Source: Michael T. Morrissey, PhD, Oregon State University Seafood Lab)
also been used to reduce cholesterol, triglyceride, and low-density lipoprotein levels in blood and to keep the circulatory system normal. With anti-aggregatory properties, EPA helps to lower blood viscosity and is used as a potent antithrombic agent. Some species examined from Indian coastal regions are rich sources of EPA and DHA and are being used in better recovery of cardiac problems. Potent medicines, prepared from such species as the air-breathing fish, mudskipper (Bolephthalmus boddeaerti), a bivalve (Macoma birmanica), and a gastropod mollusk (Telescopium telescopium), have been marketed globally.
The horseshoe crab, Limulus polyphemus, is also useful to humans. The hemolymph of the horseshoe crab is important in homeopathic therapies. Horseshoe crab extract has a number of applications to treat mental exhaustion, gastroenteric symptoms, cholera, and drowsiness after sea bathing. Traditionally, the tail tip is used for healing arthritis or other joint pains in West Bengal, India.
Corals are known for their beauty, but some may also be useful for their brawn. Several coral species have been successfully tested as bone substitutes to repair fractures in healing or to replace joints deformed by arthritis. Some species of coral resemble human bone and closely match human bone when implanted, allowing blood vessels to develop within them and acting as scaffolding for new bone to form.
Marine organisms are rich with many enzymes that have unique functions. Aerobic bacteria, for example, produce several enzymes, such as amylases, which are well recognized to have applications in various industries. A mutant of the amoeba Trichospaherium sp. is found to degrade and destroy plastic in the field as well as in the laboratory. Viral DNA polymerase produced by Thermococcus litoralis, a type of archebacterium, is active for more than two hours at 100°C. Enzymes isolated from extremophiles have greater stability and are longer- lasting at high temperatures than those now used by industry. Their availability would open up new possibilities for efficient manufacturing.
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Deep sea compounds in development for medical use. (Courtesy of Sara Maxwell, Marine Conservation Biology Institute)
Studies from the Orissa coast of India report that a few potent strains of marine organisms could produce novel enzymes like amalyse, protease, cellulase, L- asperginase, acetylcholinesterase, and urethanase. The results indicate that these microorganisms show potential for the production of salt-tolerant enzymes that could be used in the biotech-based food, beverage, and pharmaceutical industries.
Many toxins could become valuable medicines as analgesics and muscle relaxants. Some of these even demonstrate potential antitumor activity. Thus halitoxin—produced by the marine sponge Haliclona—inhibits the growth of certain types of tumors. Toxins that cannot be used as medicines because of their severe side effects can nevertheless be used in drug research. Some have been exceedingly valuable in studies of nerve impulse transmission and smooth muscle action. Tetrodotoxin, which is produced in specialized glands of the pufferfish and by certain marine bacterial species, acts to paralyze the peripheral nerves. It is being used in research to elucidate the nerve excitation mechanism. Lophotoxins, produced by gorgonia laphogorgia, inhibits nerve-stimulated contraction of muscle.
Biotechnological prospecting of the marine environment for microorganisms is still in its infancy. Several microorganisms are of considerable current interest as new, promising sources of metabolites and enzymes with the potential for unsuspected applications. There is the possibility of producing future drugs from several marine organisms such as algae, sponges, jellyfish, corals, shellfish, oyster, yeast, and fungi. The future for bioactive marine products for human health is bright.
This article was published in Drug Discovery & Development magazine: Vol. 10, No. 2, February, 2007, pp. 46-49.
Filed Under: Drug Discovery