Antimicrobial secondary metabolites from marine fungi: A mini ... - NOPR

Indian Journal of Geo-Marine Sciences Vol.45(9), September 2016, pp. 1067-1075

Review Article

Antimicrobial secondary metabolites from marine fungi: A mini review Vivek K. Bajpai* Department of Applied Microbiology and Biotechnology, School of Biotechnology, Yeungnam University, Gyeongsan, Gyeongbuk 712-749, Korea *[E-mail: [email protected]] Received 30 June 2014; revised 17 July 2014 Marine fungi living in a stressful habitat, under cold, lightless and high pressure conditions have shown significant importance as new promising sources of biologically active products. These marine fungi produce fascinating and structurally complex natural products. To date, only a minimum amount of microorganisms have been investigated for the production of bioactive marine metabolites with unique structural skeletons. Marine microorganism based secondary metabolites are considered to be a burning area of research in few last decades. Many of such compounds have been proven to be anti-bacterial, anti-fungal, anti-algal, anti-HIV, anti-helminthic, anti-protozoan, anti-tumor and anti-allergic agents. Marine fungi have been reported to be the producers of such compounds owing to their multitude of defense mechanisms and complex metabolism. Although a number of natural products have been isolated from marine microbial flora, a limited number of compounds have reached to the clinical trial levels as a drug. Herein this review we have discussed recent studies on the isolation, characterization and the pharmacological significances of anti-bacterial, anti-fungal and anti-infective agents of marine fungal origin. Further, the clinical status of such compounds has also been discussed in comparison with those derived from their terrestrial counterparts. This review provides research insights so far conducted on marine fungi with aspects to provide baseline information on marine flora-based antimicrobial research which may assist in context to provide cheaper, safer, and potent medicinal alternatives to challenge the dreadful human disease. [Keywords: Marine fungi, Antimicrobials, Secondary metabolites, Mycotoxins, Ecology]

Introduction It has been known for thousands of years that marine organisms possess chemical compounds capable of potent biological and therapeutic significance. However, the first true research of marine microflora started only half a century ago followed by a rigorous research investigation on all forms of life in the marine environment including bacteria, algae, sponges, fungi, corals, and ascidians, for natural product isolation. Marine world has provided a useful platform where marine organisms are significantly exploited for the production of useful products of human use. Nowadays, various pharmacological and therapeutic products of medicinal importance are obtained and actively sought from the marine world1-6. Moreover, natural compounds have high affinity to the target molecules which make them more efficient as drugs. Protein binding nature of these molecules with little loss of entropy, sustain their bioavailability and further enhance their suitability as significant pharmaceutical drugs. As reported previously, there are valuable reviews dealing with marine fungi and flexibility of marine fungal metabolites to acquire

different conformations in crucial aquatic environment makes them the compounds of choice over their synthetic availability7,8. These natural compounds are not only used by themselves but also serve as lead compounds for chemical and genetic manipulation for medicinal purposes9. Marine fungi have attracted huge research attention from the last two decades. Furthermore, the chemistry of marine has shown structurally diverse range of metabolites and related to that of terrestrial fungi10. A number of compounds of biological significance such as cytoglobosins and halovirs have been isolated from marine fungi, giving a further lead to exploit marine fungal biodiversity in order to isolate more effective and remarkable compounds from marine fungi with multitude of biological potential11. Due to the adverse living conditions, salinity, nutrition, higher pressure, temperature variations, competition with bacteria, viruses and other fungi, marine fungi have proved to be wealthy sources for the isolation of new biologically natural products12, and may have developed specific secondary metabolic pathways compared with terrestrial fungi13. A number of antibiotic compounds of medical and therapeutic

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INDIAN J. MAR. SCI., VOL. 45, NO. 9 SEPTEMBER 2016

importance have been isolated from filamentous fungi. Current scenario of research investigations on marine filamentous fungi for the isolation of biologically active secondary metabolites has confirmed a remarkable potential of them as a source of new marine drugs14. Significant research efforts on marine based fungi have resulted in the discovery of about 272 new natural products with about 240 new structural moieties, confirming that marine based fungi have a significant potential to serve as a rich source of pharmaceutical leads. Hence, this review is an attempt to describe the antifungal and antibacterial potential as well as pharmacological and biological significance of marine fungi based active compounds by considering the latest advancements and developments. Ecology and effects of fungi in the marine environment Fungi are eukaryotes and considered heterotrophic in nature. Marine fungi play a significant role in the decomposition of dead plant tissues including cellulose and lignin, and less effectively to animal tissues such as keratin and chitin15. The decomposition products are distributed in the marine water and provide back essential nutrients into the ecosystem. Due to significant and diverse biological and biochemical phenomena, marine fungi have potent ability to utilize various solid substrates for decomposition process15. Although several ecological roles of fungi in the terrestrial ecosystem have been described and thoroughly studied, the ecology of fungi in the marine environment has been remained unfolded to a certain level. The following sections highlight several examples that will illustrate the significance of fungi in marine ecosystems. A number of studies involving the ecology of marine fungi have been performed due to the pathogenicity of certain fungal species15. For instance, development of Caribbean sea-fan mortalities has been attributed to infection caused by pathogenic fungal species of Aspergillus16. A huge amount of importance has been given to marine biotechnology based on the unique properties of the marine environment. Moreover, a good adaptation of ecosystem can help to develop novel genes and the biotechnological production which may influence by the special adaptations of organisms to their environment17. However, following physical

factors may influence the marine fungi which include salinity, pH, low water potential, high concentration of sodium ions, low temperature, oligotrophic nutrient conditions and high hydrostatic pressure, being unique to the deep-marine environment18. Marine fungi have not been explored to the certain extended levels than their terrestrial counterparts, specifically those which are used frequently in the treatment of human diseases as well as several others which are used in various biotechnological applications19. This resulted to provide pioneering research insights reviewed so far on marine fungi and their bioactive compounds. Literature studies have shown that marine-derived fungi have been recognized as one of the significant sources for new biologically active secondary metabolites including anti-tumor, antibacterial, antiviral, antifungal, antiinflammatory and anticancer activities as well as the source of novel compounds as enzyme inhibitors. Recently it has been reported that a clodepsipeptide isolated from the marine fungus, Clonostachys sp. showed potent anticancer activity13. From last few decades, marine fungi have attracted huge attention for the production of marine-based secondary metabolites of pharmaceutical importance. Recent investigations on marine filamentous fungi for the production of marine fungal metabolites reflected their tremendous potential as a source of new pharmaceutical drugs even they possessed the compound of interest at low concentration with diverse biological funcation17. Pioneering researches on marine microflora demonstrated that they may be considered unlimited sources for the production of novel biologically active compounds. In particular, marine-based fungi have yielded an increasing amount of biologically active secondary metabolites as natural products. Update review of new bioactive natural products from marine bacteria and fungi A highly complex marine environment possesses enormous amount of diversity of life forms8. Marine fungi with huge amount of medicinal importance are considered novel and rich sources of biologically active products, living in intimate association with soft-bodied marine organisms, which lack true structural defence mechanisms, and thus rely on chemical defence by production of bioactive secondary metabolites, either by themselves or by associated microflora, to survive in their extreme

BAJPAI et al.: ANTIMICROBIAL SECONDARY METABOLITES FROM MARINE FUNGI: A MINI REVIEW

habitat20. From the last few years, amount of reported secondary metabolites from marine fungi has increased rapidly21,22. As reported previously, about 961 new compounds were isolated in the year 2007 from marine fungal species reflecting an about 24% increase as compared to the compounds reported for the consecutive year 200621. Further, exploitation of other selected marine bacteria and fungi was enhanced for the production of new secondary metabolites living in association with marine microorganisms such as sponges, algae and mangrove plants. Moreover, special emphasis on these bioactive marine secondary metabolites was given with defined modes of their action, as well as source organisms and place of origin23. Antimicrobial active compounds from marine fungi Marine fungi produce diverse range of biologically active secondary metabolites which obtained from variety of marine substrates including marine sponge and fish as well as from primary producer, with significant amount belonging to mangroves, sea grasses and algae. This group of marine microorganisms has attracted considerable amount of research attention especially from the research groups working on natural product chemistry, and plethora of studies dealing with diverse and unique compounds of marine fungi have been reported, with pertinent biological activities including antimicrobial, anticancer, anti-inflammatory and antiviral properties15, 24, 25. After the discovery of penicillin in early nineteen century, plethora of studies, specifically on soil-based bacteria and fungi, demonstrated that microorganisms are a rich source of structurally diverse compounds with profound biological and therapeutic significance27. The increasing demand for new antimicrobial agents made it possible to control emerging diseases or resistant pathogenic microorganisms resulting in a growing number of researches to explore the marine world for new bioactive compounds. Continuing and pioneering efforts were made to develop extensive screening programs worldwide aiming of the isolation of new biologically active metabolites from marine microorganisms. The outcomes of the extensive researches for decades confirmed the diversity of the natural products from marine fungi with a potential for using these compounds in clinical trials for future

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development of anti-infective drugs1. Antimicrobials from marine fungi Marine fungi have been extensively studied and represent a huge portion of antibacterial compound producers among the members of marine microbial flora. Recently Xiong et al. (2009) 28 reported the bioactive potential of marine fungus Cladosporium sp. F14 with number of reported biologically active compounds including methanephrine; cis-1- chloro-9octadecene; 16-nitrobicyclo[10.4.0]hexadecane-1-ol13-one; 13-bromotetradecanoic acid; 2-phenazinol, 6amino-; morphinan-2,4-diol-6-one,N-formyl-; and pyrrolo[1,2-a]-pyrazine-1,4-dione, and hexahydro-3(phenylmethyl) with antibacterial activity against 6 bacterial species including Bacillus sp., Vibrio sp. and Micrococcus sp.28. Similar study conducted on Cladosporium sp. resulted in the isolation of another compound, cladospolide E, a nine-membered lactone, which showed potential of antibacterial activity against several pathogenic bacteria including E. coli, Bacillus thuringiensis, B. subtilis, Mycobacterium smegmatis, and S. aureus29. Furthermore, a compound 6-oxo-de-O-methyllasiodiplodin was isolated from a brown alga endophytic fungus (ZZF36) from the South China Sea, characterized as a polyketide, which was found to exert significant antibacterial effect against B. subtilis, S. aureus and Salmonella enteritidis30. Further study was conducted on a marine-derived fungus, Cladosporium sp. F14, in order to confirm its great potential for the production of antibiotic and antifouling compounds on different cultivation media. The fungus was able to grow with rigorous growth on tryptone or yeast extract media, however slow growth pattern on ammonium or nitrate media, with no growth on urea media. Incorporation of glucose or xylose to cultivation media resulted in the enriched production of antibiotic and antifouling compounds from Cladosporium sp. F14. However, no production of antibiotics or biologically active compounds was observed in the absence of the sugars, even though the fungal cells grew well under these conditions. In addition, fungal extracts with metabolic profile decreased the attachment of bryozoan larvae Bugula neritina and showed antibiotic activity against number of pathogenic bacteria. This confirmed that marine fungus has the ability to produce antibiotic and antifouling compounds31. With reported evidences, it has been confirmed that marine fungal

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speices of genera Pencillium and Cladosporium display significant antibacterial activity32. Moreover, Nigrospora sp., a marine-based fungus isolated from Similan Island in Thailand, represented the first example of marine derived Nigrospora sp., since these fungal species are known to grow as plant endophytes only. Nigrospora sp. resulted in the isolation of four new marine metabolites called nigrospoxydons A–C (Fig. 1) and nigrosporapyrone, with nine known compounds in potato dextrose agar (PDB) medium. In addition, crude fungal extracts Nigrospora sp. displayed potent antibacterial activity against standard S. aureus ATCC 25923 (SA) and methicillin-resistant S. aureus with MIC value ranging from 64-128 mg/ml33. Only a known compound (+)-epoxydon with a new compound (25) displayed antibacterial efficacy against both standard and MRSA strains, while remaining compounds had no antibacterial effect against the tested pathogens. During the assay, compound 25 found highly effective than compound 29 against standard strains with MIC value of 152.38 mM, however showed less susceptibility against MRSA strains with MIC value of > 304.76 mM. The MIC value of compound 29 remained to be 820.51 mM against both types of tested strains33. The fungal broth of a marine Aspergillus species isolated from the surface of the marine brown alga Sargassum horneri in Korea yielded a new polyoxygenated decalin derivative, dehydroxychlorofusarielin B (30), which was found to exhibit mild antibacterial activity against S. aureus, methicillin-resistant S. aureus, and multidrugresistant S. aureus with MIC values of 142.36 mM for all tested pathogens34. Moreover, when assessed the antibacterial efficacy of 2,2,7-trimethyl-2H-chromen5-ol (1) first time, the compound displayed less antimicrobial effect against B. subtilis, Candida albicans and Saccharomyces cerevisiae, and mild inhibitory effect against Schizosaccharomyces pombe but had no activity against Escherichia coli 35. Fungal species belonging to genus Penicillium are known to produce a huge variety of compounds with a wide range of biological and pharmacological activities. The fungal broth of a marine-derived fungal species PSU-F44 of genus Penicillium isolated from Annella sea fan yielded two new metabolites, penicipyrone and penicilactone, together with three known macrolides (+)-brefeldin A(+)-brefeldin C and 7-oxobrefeldin A. While testing the compounds

penicilactone, brefeldin A and 7-oxobrefeldin A for antimicrobial activity, compound brefeldin A displayed strong antifungal activity against M. gypseum SH-MU-4 with MIC value of 228.57 mM, whereas the remaining compounds were inactive (MIC > 700 mM). However the MIC value of all the tested compounds against the tested pathogen of methicillin-resistant S. aureus SK1 was found to be > 700 mM36.

Fig. 1-Chemical structures of antibacterial compounds isolated fro m marine fungi.

Antifungals from marine fungi Symbiotic feature among the marine microorganisms is known to be an excellent phenomenon for the production of biologically active compounds. Scientific reports have confirmed that a compound xestolactone B, isolated from marine fungus Penicillium cf. montanense associated with the sponge Xestospongia exigua, displayed significant amount of antifungal effect against filamentous fungal pathogens of C. albicans37. Moreover, a anthracycline related pentacyclic compound, seragikinone A, isolated from an unidentified marine fungus derived from the rhodophyte Ceratodictyon spongiosum displayed mild antifungal effect against C. albicans38. As reported previously, a few marine fungal species belonging to the genus Aspergillus, Pencillium and Fusarium isolated from mangrove yielded in the isolation of various fungal metabolites. Upon testing, these fungal compounds showed potential antimicrobial effect against E. coli, K. pneumonia, P. aurogenosa and M. tuberculosis H37 RV39. A fungal strains Zopfiella marina of marine origin has been reported to produce zofimarin an antifungal diterpene glycoside, whereas another antifungal agent griseofulvin has been reported to yield from a marine fungus Penicillium waksmanii40. Marine endophytes Chaetomium sp. of algal symbiosis resulted in the isolation of three new fungal polyketide metabolites, chaetocyclinones, together with three known compounds. The antifungal activity


of chaetocyclinone A (Fig. 2) was tested against selected phytopathogenic fungi, and this compound displayed dose-dependent antifungal activity against Phytophthora infestans41, none of other new compounds displayed antimicrobial effect41. It was found in this study that no cytotoxicity against the tumor cell lines including HM02 (stomach), HepG2 (liver) and MCF7 (breast) were observed upto 28.7 mM. The 13C-labelled acetate-based biosynthesis of compound 45 suggested that the compound to be derived from the polyketide pathway41. Moreover, a marine-derived fungus Ampelomyces sp. was reported to produce antimicrobial compounds42. In addition, a marine sponge Myxilla incrustans derived fungus Microsphaeropsis sp. yielded an eremophilane derivative, microsphaeropsin with potent activity against Ustilago violacea and Mycotypha microspora43. Modiolides A–B produced by the marine fungus of Parapha eosphaeria, have been found to be potent macrolides against Neurospora crassa 44. The great potential of marine organisms as significant antibiotic producers has been further confirmed by others45. It was reported that crude culture solvent extract of fungal species Fusarium sp. 05JANF165 showed remarkable antimicrobial efficacy. The results of preliminary screening from Fusarium sp. yielded a new antifungal compound Fusarielin E with confirmed structure elucidation45.

Fig. 2-Chemical structures of antifungal compounds isolated from marine fungi.

Antivirals from marine fungi The extensive research on marine fungi has revealed interesting insights on the search for antiviral compounds of marine origin (Table 1). Marinederived fungal species such as Fusarium heterosporum and a Phoma sp. yielded promising marine metabolites equisetin and phomasetin, respectively, which have displayed significant HIV-1

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integrase inhibition in bioassay-based experiments46. A cyclic depsipeptide, sansalvamide A, isolated from the marine fungus Fusarium sp., has shown inhibition of pathogenic poxvirus Molluscum contagiosum by preventing topoisomerase catalyzed DNA relaxation, DNA-binding and covalent complex formation47. This compound displayed significant therapetutic potential as antiviral drug since poxvirus can cause severe lesions in AIDS patients1. A marine fungus Scytidium sp. has yielded number of novel linear peptides, halovirs A–E, which have exerted potent antiviral efficacy against HSV-1 and HSV-248. The ED50 values of these liner peptides were found in the range of 1.1- 3.1 M. Although during standard plaque reduction assay, halovir A was able to equally inhibit the replication of HSV-1 and HSV-2 with an ED50 value of 280 mM, the mode of action is still not clear. It is speculated that halovirs A renders HSV noninfectious by possible membrane destabilization48.

Fig. 3-Chemical structures of antiviral compounds isolated from marine fungi.

In addition, a novel terpenoid, stachyflin isolated from the fungus Stachybotrys sp. RF-7260 displayed significant antiviral activity against influenza A virus (H1N1) in vitro as compared to other anti-H1N1 drugs including amantadine and zanamivir with an IC50 value of 0.003 M49. Stachyflin as a pentacyclic terpenoid possesses a novel cis-fused decalin, and inhibition of fusion between the viral envelope and the host cell membrane is considered to be the right pathway to its antiviral mode of action which is thought to be unique feature among antiviral compounds49. A new difuranxanthone, asperxanthone and a new asperbiphenyl (Fig. 3), reported from a fungal strain, identified as Aspergillus sp. (MF-93) have been found to display moderate inhibitory activity by 62.9% and 35.5%, respectively against a typical tobacco mosaic virus of the tobamovirus group50. In addition, a 12-membered new macrolide

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Compound Antibacterial Siccayne & deacetoxyyanuthone A


Table 1- Antibacterial, antifungal and antiviral compounds derived from marine fungi. Organism Activity against Reference

Penicillium sp.

Gram +ve bacteria Methicillin and multidrug resistant

Ascochital

Kirschsteiniothelia maritima

Bacillus subtilis

Enniatin B Seragikinone

Fusarium sp. Unidentified marine fungus

S. aureus and Vancomycin resistant S. aureus; M. luteus

Bugni and Ireland, 2004 Jiang et al., Shigemori et al., 1999

Neomangicol B

Fusarium sp.

Corynebacterium xerosis

Renner et al., 1998

3-alkylpyridinium

Unidentified marine fungus

Antibacterial

Ana Zovko et al., 2012

Trichoderma konongii Penicillium viridicatum Rhodophyte ceratodictyonspongiosum

Antifungal Antifungal

Xestodecalactone A

Penicillium cf. montanense

Antifungal

3-alkylpyridinium

Unidentified marine fungus

Chaetocyclinone A Verticinols A Polyesters

Chaetomium sp. Verticillium tenerum Hypoxylon oceanicum

Candida albicans, Baker’s yeast S. cerevisiae, Wallemia sebi. S. cerevisiae Antifungal Antifungal Antifungal

Penicisteroid A

Marine alga derived fungus

Antifungal

Mi-Hee et al., 2008 Mi-Hee et al., 2008 Punyasloke et al., 2006 Punyasloke et al., 2006 Unidentified marine fungus Losgen et al., 2007 Almeida et al., 2010 Schlingmann et al., 2002 Goa et al., 2004

Ascomycetes Aspergillus sp. Fusarium heterosporum Scytidium sp. Stachybotrys sp. RF-7260 Scytidium sp. Marine endophytic fungus Emericella sp. Marine endophytic fungus Emericella sp.

Antiviral Antiviral Antiviral against HIV HSV-1 and HSV-2 Influenza A virus (H1N1) Halovirus

Muftah et al., 2004 Wu et al., Singh et al., 1998 Rowley et al., 2003 Minagawa et al., 2002 David et al., 2003

Influenza A virus (H1N1)

Zhang et al., 2011


Zhang et al., 2011


Zhang et al., 2011

Antifungal Trichodermaketone A Fumigaclavin Seragikinone A

Antiviral Balticolid Asperxanthone Equisetin Halovir A-E Stachyflin Peptides Emerimidine A and B Emeriphenolicins A and D, Austin, austinol, dehydroaustin,

Marine endophytic fungus Emericella sp.

Antifungal

balticolid isolated from the culture broth of fungal strain Ascomycetes sp. 222, confirmed as (3R,11R), (4E,8E)-3-hydroxy-11-methyloxacyclododeca-4,8diene-1,7-dione on the basis of spectral data analysis showed a moderate anti-HSV-1 activity with an IC50 value of 0.45 μM51. Mycotoxin producing marine fungi Xu et al. (2013)52 reported that marine gorgonian derived fungus Aspergillus sp. SCSGAF0093 yielded in the presence of four new (1-4) mycotoxins including six aspergillic acid group toxins, naluminiumneoaspergillin (1), zirconiumneoaspergillin (2), aspergilliamide (3), ferrineoaspergillin (5), flavacol

Li et al., 2005

(6), neoaspergillic acid (7), and three ochratoxins, ochratoxin A n-butyl ester (4), ochratoxin A (8) and ochratoxin (9)52. It was conferred to be the first report on zirconium complex obtained from nature and ochratoxins isolated from marine environment, and the biotoxicity of compounds 1–9 was determined by brine shrimp lethality bioassay with LC50 value ranging from 2.59 to 205.67 µM. Various species of Aspergillus such as A. ochraceus, A. niger, A. carbonarius, and A. flavus, able to produce variety of mycotoxins including ochratoxin A are also widespread in marine environment53,54. Marine biotechnological approaches such as bioaccumulations have made easy transformation of


ochratoxin A into marine organism. Fish and seafood are considered vital ingredients of human diet and consumed worldwide55 as confirmed by their huge amount of consumption 16.3 kg per year in 2002, which increased by 18.6 kg per year in 201055,56. At microconcentration, ochratoxin A is considered as a nephrotoxin to all animal species57.which has raised a serious issue of seafood pollution by ochratoxins. However no serious results have been observed so far on the presence of ochratoxins contents in seafood or marine food products. Houjin et al. (2011)58 reported a marine fungus Aspergillus sp., isolated from soft coral Sarcophyton tortuosum, which was able to produce a mycotoxin called penicillic acid58, and it was also suggested that monoterpene, α-pinene as a substrate could be used to be an elicitor for the production of mycotoxin58. In addition, penicillic acid can also be able to alter the oxidase activities, trigger and modulate microbial metabolic pathways, with a potential in fermentation process58. Pharmaceutical and industrial importance of marine fungi derived antimicrobial agents Lack of scientific knowledge and specific favorable conditions for the growth and cultivation of marine micro- or macro-organisms have been emerged as major drawback to pharma and medicine industries to make the marine based drugs available at commercial levels. Obstacles to collect samples from deep sea environment have made great difficulties in the research of drug discovery from marine environment, hence only the substrate samples available at superficial and sea-shore with easy access have been exploited for marine drug discovery59. However, recent development in marine biotechnological setups have made ease to research on marine drug discovery providing great advanced tools and technique to allow for more efficient and systematic explorations of extreme environments59. Since number of shortfalls and hindrances associated with the isolation and characterization, sample supply and environmental considerations, discovery of novel marine natural products of therapeutic importance has become a great challenge to researchers. Only few selected marine based compounds or drugs after preclinical trials at laboratory level are referred to clinical trials which might be due to low supply, lack of knowledge, lack of financial funds, ignorance and even the lack of orientation or high toxicity of the isolated

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compound60. Various biologically active compounds to serve as antimicrobials such as penicillins, cephalosporins, aminoglycosides, tetracyclines, and polyketides have been isolated from terrestrial microorganisms. An oral drug cefditoren, a derivative of cephalosporin has been isolated from Cephalosporium species with an ability to rapidly hydrolyze by intestinal esterase to the microbiologically active form. Moreover, cefditoren has been found to exhibit multitude of biological activities against number of pathogenic bacteria including both Gram+ and Gram- bacteria. In addition, it has also been reported to work against the infections of acute bacterial exacerbation of chronic bronchitis (AECB), group A beta-hemolytic streptococcal pharyngotonsillitis, and uncomplicated skin/skin structure infections 61. Also a bacterial cyclic lipopeptide daptomycin isolated from Streptomyces roseosporus has been found to work effectively for the treatment of complicated skin and skin structure infections which binds to bacterial cell membranes and then disrupts the membrane potential, leading to blocking of the synthesis of proteins, DNA, and RNA62. A marine fungus Coleophoma empetri has been yielded an antifungal micafungin sodium which has been found to inhibit (1,3)-dglucan synthase of fungi63, 64. Micafungin also exhibited considerable amount of antifungal activity against a panel of azole resistant Candida species and Aspergillus species63. A brief description of major industrially important antibacterial, antifungal and antivirals has been given in Table 1. A major hurdle has been reported in marine drug discovery for the compounds that are extremely difficult to separate which include the presence of closely related multiple bioactive compounds leading to a very complicated isolation process. However, chromatographic separation has significantly helped in this regard to achieve a good separation of biologically active compounds from a sample of mixture. Moreover, methodologies based on green analytical chemistry should be revised and to achieve good quality of extraction and separation of bioactive compounds from marine fungi in order to reduce the amounts of solvents at easy cost processing. Nowadays systematic information on tools and techniques used for extraction purposes and isolation of bioactive compounds from marine microorganisms has been reviewed significantly7.

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