Novel drugs from marine microorganisms

Critical Reviews in Microbiology, 2011; 37(3): 245–249 © 2011 Informa Healthcare USA, Inc. ISSN 1040-841X print/ISSN 1549-7828 online DOI: 10.3109/1040841X.2011.576234

Review Article

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Novel drugs from marine microorganisms Faraza Javed1, M. Imran Qadir1, Khalid Hussain Janbaz2, and Muhammad Ali3 College of Pharmacy, Government College University, Faisalabad, Pakistan, 2Department of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan, and 3Institute of Biotechnology, Bahauddin Zakariya University, Multan, Pakistan 1

Abstract Marine microorganisms have expected mounting consideration on the basis of bioactive metabolites and propose an exclusive prospect to both enhance the amount of aquatic natural foodstuffs in clinical trials as well as speed up their progress. This review focuses particularly on those molecules, originated from marine microorganisms, presently in the medical pipeline that have been recognized or highly expected to be identified based on growing incidental evidence. Particularly karlotoxin class compounds, isolated from dinoflagellate Karlodinium veneficum, offer chances to create new molecules for control of cancer and high serum cholesterol levels. Keywords: Marine microorganisms, Bioactives, Aquatic foodstuff, Biofilms

Introduction

et al., 2007). However, it is significant to carry out a vital research on marine environment in order to authorize the persistent identification of distinctive microorganisms. An emerging source of the new bioactive may result from many modern studies of microbial diversity in marine environment, chiefly those microbes which couple with marine animals and plants. Several researches have confirmed that “living surfaces” symbolize an environment which is rich in the epibiotic microorganisms that synthesize bioactive. Nevertheless, the enormous biotechnological prospective of the marine epibiotic microorganisms has remained unexplored. There is still limited knowledge of the physiological requirements of most marine microorganisms. Nevertheless a greater understanding of their conditions for growth will offer new insights into the complex world of marine microbiology (Guo et al., 2002). Consequently, a greater investment in the development of marine biotechnology will produce novel compounds that may contribute significantly toward drug development over the next decade. We have discussed the importance of exploring new sources potentially rich in bioactives, and highlight the significance of considering the chemical ecology of marine microorganism-host associations for the targeted isolation of bioactive producing microorganisms. Inspection of medical proposition by the source has confirmed that

Drug development is a very important component of microbiology (Qadir and Malik, 2010; Qadir and Malik, 2011). While oceans cover more than 70% of Earth’s surface, aquatic derived microbial natural foodstuffs have been chiefly unexplored. The aquatic environment is a home for various exclusive microorganisms, which generate biologically active complexes called bioactives. Plants and their extracts have been utilized for the management of various human diseases for millennia, and their use has also been recorded in most ancient archaeological resource (Penseyan et al., 2010; Newman et al., 2000). In contrast, the discovery of microbes as manufacturer of therapeutically agents began in the 20th century. However, despite this short history, almost 10% of all presently known biologically active natural foodstuffs/ products are of microbial origin. These include majority of antibiotics, visibly indicating the potential of microbes as a rising and promising source for the creation of biologically active products (Newman et al., 2003). Definitely, by the 20th century, microbial resultant bioactives had become the basis of recent pharmaceuticals. Over the past decade, marine microbes have been acknowledged as a significant and untapped source for novel bioactive complexes and compounds (Hentschel

Address for Correspondence: M. Imran Qadir, College of Pharmacy, Government College University, Faisalabad, Pakistan. E-mail: [email protected] (Received 05 March 2011; revised 25 March 2011; accepted 25 March 2011)

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246 Faraza Javed et al. natural foodstuffs and correlated drugs are used to treat 87% of all sorts of human diseases, including as anticancer, antibacterial, anti-parasitic, anticoagulant, and immunosuppressant agents, and so on. Up to 2000, there was no entry of any innate or natural foodstuffs or related drugs for 7 drug categories: antihistamine, antianginal, anesthetics, chelator, anxiolytic and diuretic, antidote, and hypnotics (Oftedal et al., 2010; Cabrita et al., 2010). In case of antibacterial agents, natural products and other foodstuff have made major contributions as either direct treatment or model for synthetic modifications. More than 79% of the drugs that became commercially available in the United States or were officially approved worldwide from 1982 to 2002 can be traced from a natural product origin based on species studied. Most of new compounds reported from the marine microorganisms have been found from those species that might be isolated from both sea and land. Although all these facultative species of marine are undoubtedly a good source of new metabolites, their degree of adaptation and ecological roles to the marine environment is mostly unknown (Jayakumar et al., 2010; Kobayashi et al., 1997).

Drug Discovery From Marine Microorganisms 1. Marine bacteria Majorly marine bacteria are discussed according to the sea water requirement or specifically sodium for their growth. When marine bacteria which are separated from the surface of invertebrates and marine algae, undergoes the process of screening, we recognized that grand proportion of bacteria generates antimicrobial metabolites. In 1996, the 1st antibiotic was produced by the marine bacteria (Cuevas and Francesch, 2009; Ocio et al., 2009). Furthermore, bacteria which are found in biofilms (which is formed on the surface of the marine microorganisms) hold a greater percentage of bacteria that produce antibiotics than any other marine environment. Some marine epiphytic bacteria, joined with nutrient rich surfaces of invertebrates and marine algae have exposed the fact that they produce antibacterial secondary metabolites that actually slow down the resolution of potential competitors. Recent researches have revealed that a large number of surfaces associated-bacteria produce different antibiotics. Now days, novel cyclic decapeptide antibiotic, loloatin B, which inhibits the growth of VRE (vancomycin resistant Enterococcus), and MRSA (methicillin resistant Staphylococcus aureus) is obtained from Bacillus species isolated from marine worm in Papua New Guinea. Another new antibiotic thiomarinol is produced by a marine bacterium Alteromonas rava. Many antibiotics have been reported from Bacillus including loloatins, sesbanimides, and agrochelin from Agro bacterium pelagiomicins and pyrones from Pseudomonas (Mikami et al., 1985; Cuevas et al., 2000).

2. Marine sponges Over the past 35 years, the secondary metabolites of many marine organisms have been studied widely.

During the 1970s, a small number of chemists began to reveal and isolate novel compounds from the marine source. Researches of drug discovery from marine microorganisms have accelerated and now interdisciplinary researches are also involved like biochemistry, ecology, biology, pharmacology, and organic chemistry (Newman and Eribulin, 2007). Due to the extensive biodiversity of organisms that has found in widespread oceans and seas that cover more than 70% of the world, marine microorganisms have gained much attention. From marine microorganisms, novel and structurally distinctive secondary metabolites have isolated and recognized. As a result of this struggle, many compounds following new chemical model have been developed and launched in 2004, while most of other contestants are in clinical trials (Demydchuk et al., 2008). Sponge specific microbial societies in the marine sponges, including novel lineages and candidate phyla proved as a milestone by the discovery of phylogenetic complex. Microorganisms are more reachable than those of sea water in various ways due to which unique research prospects have been opened up. Most of marine sponges act as microbial fermentors which provide thrilling new avenues in marine microbiology and biotechnology (Harvey et al., 2007; Hoshi and Endo, 2000).

3. Marine fungi Nowadays, number of compounds derived from marine fungi are in clinical pipeline, among which Sorbicillacton A is also included. This compound is extracted from a fungus associated with marine sponge and provides an advance stage of development for medical treatment. Many marine fungi produce antioxidant compounds such as Acremonin from Acremonium species, Xanthenes derivative from Wardomyees anomalus and 4,5,6-Trihydroxy Methyphthalide from Epioeeum species. These antioxidants keep away from oxidative damages linked with diseases such as dementia, atherosclerosis and cancer. They may also be helpful as therapeutics or food additives (Peng et al., 2010). Marine Actinomycetes particularly Salinospora group within the family Micromonosporaceae, that belongs to the antibiotic producing bacteria, are very promising. These microorganisms are found to be a powerful source as anticancer agents that basically target the proteosomes function. Nereus Pharmaceutical has validated their industrial potential to develop these anticancer agents. Recently some research teams have successfully identified and isolated agricultural fungicides, shrimp feed supplement, biofertilizers and cholesterol-reducing drugs from marine microbes (Hill, 2004). All these researches are limited to those marine microbes which are easily culturable. The genome sequencing makes it possible to visualize potential metabolic and biochemical capabilities of even unculturable marine microbes. One of the future research trends must be focused on bio-active substances derived from nonculturable marine microorganisms (Baldwin, 1992). Critical Reviews in Microbiology


Novel drugs from marine microorganisms 247 Most of prokaryotes from the marine sponges have been broadly characterized while sponge-inhabiting fungi were being explored. Adolf et al. (2009) characterized and isolated a fungal strain from a wild sponge Scalarispongia scalaris (Cacospongia scalaris) originated from shallow waters, from the island of Lesvos, Northern Aegean Sea, Greece. The fungus was annotated as Alternaria sp. on the base of results of the phenotypical and molecular analysis. It exhibited almost same growth kinetics both in the absence and presence of NaCl in different kinds of growth media. The fungal antimicrobial activity was studied in vitro, antagonistic assays against both yeast (Saccharomyces cerevisiae) and bacterial (Escherichia coli, Pseudomonas species, Bacillus subtilis) strains. For all the above strains, a fact that renders this fungus a potential source of antimicrobial substances, clear inhibition zones were observed (Wang, 2008).

4. Marine nematodes A hierarchical diversity index–taxonomic distinctness index showed that the Bohai Bay and other coastal sites might be disturbed by gas and oil production and many other anthropogenic influences. In other words we can say that, an anthropogenic disturbance was affecting these components of the benthos in these locations. And most of shore sampling sites in the middle of the Bohai Sea were clean, clear and unpolluted due to the compounds secreted from marine organisms especially nematodes (Peng et al., 2007).

5. Marine Cyanobacteria It was suggested that marine Cyanobacteria had ability for induction of cell death in acute myeloid leukemia cells. About half of 41 strains of screened cynobacteria, exhibited cancerous cell death (Bachvaroff et al., 2008). Various strains of Cyanobacteria contain apoptosis activity against acute myeloid leukemia cells but provide no harm to non malignant cells, e.g., hepatocytes and cardiomyoblasts. One of its strain (M44) is specifically promising because of its activity which counteracts the safety effects of the LEDGF/p75 which is overexpressed in acute myeloid leukemia and performs its action by combining with the daunorubicin, an anthracycline anticancer drug, in AML cells which protect cardiomyoblasts from the poisonous effect of the anthracyclines. By exploring the modern researches, it may be conclude that culturable benthic Cyanobacteria from the temperate marine environments provides a promising underexploited way for novel drugs against leukemia (Place and Deeds, 2004; Peng et al., 2010).

6. Marine algae Marine algae make a series of metabolites halogenated in nature with prospective mark-able value. Structures of such compounds undergo acyclic entity with linear chains to complex and difficult polycyclic molecules. For © 2011 Informa Healthcare USA, Inc.

a few decades, their pharmaceutical and medical appliances have been explored (Van Wagoner et al., 2008). During the last years, many unique compounds were discovered, researches continued but most of the algal species were inadequately screened. The main emphasize is on the ecological role of halogenated metabolites of marine algae that has someway been ignored. New researches in this field will give new approaches to comprehend biodiversity as well as many helpful and unique insights into marine ecosystem dynamics. But the challenging target for the coming years will be to understand the interaction between halogenated compound production and environmental changes including global climate changes (Sheng et al., 2010). Recent researches have been focused on macro algae than on phytoplankton for the production of halogenated metabolites. Yet, phytoplankton might be a promising stuff as it is the foundation of the marine food chains with fast adaptation to environmental changes, which undoubtedly has consequences on secondary metabolism (Place et al., 2009; Berg et al., 2002).

7. Chitins Chitin and chitosan are biodegradeable, non-toxic, and biocompatible natural marine biopolymers. The attractive feature of these biomaterials is that, they can easily converted into other forms like gels, membranes, sponges, microparticles, scaffold, nanofibers, and nanoparticles for various biomedical applications like cancer targeting drug, gene transfer, wound dressing and tissue engineering. Recently two- or three-dimensional chitinous scaffolds from marine sponges origin have been discovered and researches on their applications are under process (Ablan et al., 2006; Luo et al., 2008).

8. Marine functional food There is a wide range of chemical and biological diversity in the marine environment. A number of materials, derived from the marine environment, have been used as food and food ingredients; the most common are alginate, marine polysaccharides: carrageenan and agar. Most recent bioactive substances like marine oils and glucosamine have been added to food list for additional health benefits. Nowadays functional foods consisting of omega-3 fats are extensively consumed with a variety of new products worldwide each year (Fantini et al., 2002; Fantini and Barrantes, 2009). In additional the omega-3 fats and glucosamine a variety of other marine materials are being developed as functional food ingredients (Agargun et al., 2004; Pandey and Sassetti, 2008).

Marine Drugs In Clinical Pipeline Many marine bacterial derived and other compounds are in clinical pipeline (Scheuer, 1996). Molecules in clinical or preclinical evaluation and prototype natural products are: Solblidotin, Tasidotin, Dolastatin,


248 Faraza Javed et al. Salinosporamide A, Bryostatin, Plinabulin, Phenylahistin, Halimide, Trabectedin, Cyanosafracin B, Eribulin mesylate, Halichondrin B, Tetronamycin, Nigericin, K41A, Manzamine A, Ircinal A, Karlotoxin. These compounds have variety in their use (Penseyan et al., 2010; Newman et al., 2000). Some others are Aplidine, Bryostatin, Didemin B, Ecteinascidin 743, Kahalaide F, Mycaperoxide B as anticancer, Cyclodidemniserinol trisulphate, Lamellarin A 20 sulphate against HIV, Dithiocyanates against nematode infection, Contignasterol for asthma and Conotoxins for pain (Rinehart et al., 1998; Yamada et al., 2000; Rinehart, 2000; Zewail-Foote et al., 1999; Kijjojoa and Sawangwong, 2004). Trabectedin is produced by symbiotic bacteria and recently approved for cancer treatment. Zalypsis and Trabectedin have prominently comparable ring system to the saframycin which is produced by bacteria. Moreover, Trabectedin could be produced semi synthetically based upon the Pseudomonas fluorescens and Cyanosafracin B (Rinehart, 2000; Zewail-Foote et al., 1999). A variant of the sponge is Eribulin mesylate which is basically isolated polyether Halichondrin B (Alchorn, 2007). Polyether produced by bacteria such as Nigericin, Tetronamycin, and K 41A have almost related structures to the compounds of Halichondrin family proposing the chances of microbial creation (Alchorn, 2007; Simons and Ehehalt, 2002).

Conclusion Marine microbiology began in the late 19th century and emerged as a very fascinating and interesting field of biology. Ocean voyages and missions held during l855 to 1890 had put down an establishment for consequent microbiological studies of the oceans. The roles of marine microorganisms in different fields like productivity, ecology, bio film, and food chain production were discovered between 1975 to 1980. After 1980, biotechnology appeared as an emerging field which gave direction to the study of marine microbes for biotechnological aspects like microbial drugs and genomic identification. These aspects gained much importance during l990–2005 and finally resulted in the production of novel products and new techniques. Now the invention of scanning electron microscope and fluorescent probes is very useful to understand the behavior and actions of bacteria. Researches are going on by using the advanced tools. A future progress of the marine microbiology is based on new instruments and methodologies yet to be built-up.

Declaration of interest No competing financial interests exist.

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