3. REVIEW OF LITERATURE

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1 19 3. REVIEW OF LITERATURE REVIEW ON ANTAGONISTIC ACTINOMYCETES Actinomycetes hold a prominent position as targets in screening programmes due to their diversity and their proven ability to produce novel antibiotics and other non-antibiotic lead molecules of pharmaceutical interest. Actinomycetes were first discovered by Ferdin and Cohn (Goodfellow, M. et al, 1984) who observed filamentous growth in secretions from lacrimal ducts of lum. Shortly after this, an organism was observed in a specimen of lumpy jaw of cattle and was described as Actinomyces bovis (Goodfellow, M. et al, 1984). The first plant pathogen Streptomyces scabies was isolated from potato scab by Thaxter (Thaxter, R. et al, 1890). The opening of the field of antibiotics of actinomycetes was marked by isolation of actinomycin (Waksman, S.A. et al, 1940) in Waksman and Woodruff reported the isolation of actinomycin, the first actinomycetes produced antibiotic to be obtained in a crystalline form. After this discovery, the attention of other investigators all over the world turned towards detailed scrutiny of the actinomycetes in screening programmes. It was followed by the discovery of streptothricin (1942) and streptomycin (Schatz, A. et al, 1944). The chemotherapy of tuberculosis was made possible with streptomycin.

2 20 Although most of the antibiotics are obtained from streptomycetes, other genera such as Actinoplanes, Actinomadura and Micromonospora also produced useful and potential antibiotics. The past work on actinomycetes and their antagonistic activities from1968 to Brianskaya and Kaliuzhnaya (Brianskaya, A.M. et al, 1968) in 1968 reported antibacterial properties of actinomycetes present in soil of irrigated fields. Tendler (Tendur, M.D. et al,1969), reported a new antibiotic from thermophilic actinomycete which inhibits the growth of penicillin and tetracycline resistant strain of Staphylococcus aureus. Kaliuzhnaia et al. (1975), isolated antagonistic actinomycetes from soil samples of Ukraine and An isolate A. chromofuscus L-721 was found to possess good antagonistic activity against anthrax bacilli. Tonew (Tonew, E. et al, 1975) reported new antibiotics with antiviral activity (streptoviridins) from Streptomyces griseofulvis. Iglot (Inglot, D. et al, 1977) isolated 55 actinomycete strains from soil samples and investigated their antagonistic properties. He reported that strains belong to 22 species, of which most abundantly represented were S.antimycoticus, S.rubiginosohelvolus, S. marcrosporeus and S. coerulesens. Among these, 16 species exhibited activity against Gram positive & Gram negative bacteria, fungi and neoplastic cells. Fleck et al. (1980) isolated naphthoquinone antibiotic, granatomycin from Strptomyces lateritus which exhibited good antimicrobial and antiviral activities.

3 21 Galatenko et al. (1982), isolated actinomycetes of the genus Actinomadura from the virgin and cultivated soils. The isolates had a moderate activity mainly against Gram-positive organisms. Fusao Tomita et al. (1983), isolated a new species named Streptomyces melanovinaceus nov. sp. from a soil sample collected in Machida-shi, Tokyo, Japan. The strain produced a novel antitumor antibiotic (DC-52) which contains the novel skeleton 8, 11- iminoazepinoisoquinonline which has been discovered in nature for the first time. The antibiotic DC-52 is active against Gram positive bacteria but not against Gram negative bacteria. The antibiotic is also active against mouse leukemia p 388. Ikemoto et al. (1983), isolated a soil actinomycete, strain TI -1 and it produced a new antibiotic aculeximycin which killed insects as well as inhibited the growth of bacteria, yeasts and molds in vitro. From its morphological, cultural and physiological characteristics, the strain was identified as Streptosporangium albidum. The production of aculeximycin was carried out by conventional submerged culture and the highest antibiotic titre obtained was 250mg/ml. Stackebrandt et al., (1983) investigated representatives from various genera of the order Actinomycetales by comparative cataloging of their 16S ribosomal ribonucleic acids to establish their phylogenetic relationships. Members of Actinoplanes, Ampullariella, Dactylosporangium and Micromonospora form one cluster that is peripherally related to the cluster defined by members of Mycobacterium, Nocardia and Rhodococcus. Streptomyces griseus and

4 22 strains of Chainia, Kitasatoa, Streptoverticillium, Microellobosporia and Elytrosporangium are phylogenitically closely related, whereas Streptosporangium roseum is more, distinctly related to this cluster, Thermoomospora curvata and Geodermatophilus obscurus represent individual clusters. This grouping of organisms is highly supported not only by data from deoxyribonucleic acid deoxyribonucleic acid homology studies and deoxyribonucleic acid - ribosomal ribonucleic acid cistron dissimilates but also by several common biochemical characteristic of proven taxonomic value. Miyashiro et al., (1983), isolated two streptothricin group antibiotics, AN-201 I and ll, from the culture broth of Streptomyces nojiriensis C-13. They had antibacterial activities against several strains of E. coli, Bacillus subtilis, Micrococcus luteus and Staph aureus and showed strong selective cytotoxic effect on 3T3 cells. Paul and Banerjee. et al (1984), reported antifungal actinomycetes from the soils of West Bengal, India. They isolated 127 actinomycetes from 47 soil samples and tested for their antifungal activities against different fungi. Only 26 were found to exert strong antifungal activity. Umezawa et al., (1984) isolated a new antitumor antibiotic, Kazusamycin from a culture broth of Streptomyces sp. No Patel et al., (1984) purified a novel, solvent extractable antibiotic complex from the fermentation broth of an unusual member of the genus Streptosporangium. Among the two components the major component was identified as a previously reported compound, 1,6-

5 23 dihydroxyphenazine. The other component was a novel chlorine containing phenazine, 1,6-dihydroxy-2-chlorophenazine, which exhibited broad spectrum antifungal activity in vitro against dermatophytes and candida. Umezawa et al., (1985) reported a novel ansamycin antibiotic, trienomycin A isolated from a streptomycete strain. Iwami et al., (1985) isolated an actinomycetes from a soil sample and identified it as Actinomadura pulveracea sp. nov. It produced new antitumor substance FR and FR Kiyoto et al., (1985) studied the activities of the above two substances FR and FR They were highly active. Experimental tumors induced in mice. They also exhibited antimicrobial activity against Gram-negative bacteria and fungi. These compounds contain sulphur in the molecule and belong to a new class of antitumor agents. Kitahara et al., (1985) isolated an actinomycetes strain, A-347 from a soil sample which produced a novel antimetabolite viz. 7- Hydroxyguanine. It inhibited the growth of experimental tumors such as L, 1210 leukemia. Gupta et al., (1986), isolated 185 actinomycetes from different types of soil samples from Agra region (India), of which 142 isolates exhibited antagonistic activity against 7 test organisms. Tunac et al., (1986) reported a novel phenazine antitumor antibiotic from Streptomyces lomondensis sub sp. Galanosa NRRL The antibiotic is selectively active against Streptococcus

6 24 pneumoniae (MIC<0.46 µg/ml) and active murine P 388 leukemia in T/C 149. Takahasi et al., (1986) isolated a novel antitumor antibiotic DC-86-M from the culture broth of Streptomyces luteogriseus DO-86. The antibiotic has the molecular formula C17 H14 N2 O5 and belongs to the phenazine antibiotic. It is active against murine sarcoma 180 and also against Gram positive and Gram negative bacteria. Mishra et al., (1987) screened 942 microbial isolates for insecticidal and nematicidal metabolites which included 302 streptomycetes. Kobayashi et al., (1987) reported a new oligomycin, oligomycin E, an antitumor antibiotic from the culture broth of a Streptomyces species MC I Oligomycin E was found to be more active when compared with other oligomycins. It is active against HeLa cells. Takizawa et al., (1987) isolated a new pyrrole-amidine antibiotic TAN A from culture broth of Streptomyces idiomorphus sp.nov. The antibiotic is active against bacteria, fungi and a protozoan and has cytotoxic activity against murine tumor cells. Kawai et al., (1987) isolated a new anthracycline antibiotic, arugomycin from the culture broth Streptomyces violaceochromogenes. Takeuchi et al., (1988) reported new antifungal antibiotics, benanomycins A and B having a benzo [a] napthacene quinine skeleton from the culture broth of actinomycete sp. MH F which is related to Actinomadura.

7 25 Ohkuma et al., (1988) isolated an antibiotic complex (BMY ) from the culture filtrate of Streptoalloeeichus hindustanus sp nov. The antibiotic complex consists of tallysomycins A and B and exhibited weak activity against Gram positive and Gram negative bacteria. It exhibited strong activity towards herpes simplex virus type I (HSV-I). Prokop et al., (1988) reported Arizonians, a novel complex of antibiotics related to kalafungin from the fermentation broth of Actinoplanes Sp AB 660 D-122. Two members of the complex, arizonins A1 and B1 exhibited moderate to potent in vitro antimicrobial activity against pathogenic strain of Gram positive bacteria. Nakamura et al., (1989), isolated two species of the genus kitasatosporia from soil samples capable of producing carbapenems antibiotic. Naruse. et al (1989) isolated a new peptide antibiotic, lanthiopeptin from the culture broth of streproverticillium. It exhibited good antiviral activity. Galatenko and Terekhova. et al (1990) devised a selective procedure for the isolation of rare actionomycetes from soil samples. Preliminary exposure of the soil suspensions to UV light was done which resulted in the isolation of 2539 strains of actinomycetes belonging to different genera. Population of Micromonospora, Amycolatopsis and Nocardia increased while Streptomycetes were

8 26 markedly decreased. Whereas 2-3 fold increase in the occurrence of Micromonospora was observed. Hatsu et al., (1990) isolated an antibiotic S2487 from the culture broth of actinomadura species during the course of searching for new antiviral antibiotics from of soil microorganisms. Sing Lam et al., (1990) isolated an actinomycete from a soil sample collected in India. Taxonomic studies on this strain indicated that it was streptomyces hygroscopicus and was found to produce a new antitumor antibiotic, himastain.. Himastain showed antimicrobial activity against Gram positive bacteria but it was inactive against Gram negative bacteria. Himastain prolongs the life span of mice inoculated with P388 leukemia and B16 melanoma. Hara et al., (1990) isolated a group of new Antitumor antibiotics, kapurimycins from a streptomyces sp.do-115. The kapurimycins were active against Gram positive bacteria and HeLa S3 human cervical cancer cells and T24 human bladder carcinoma cells in vitro. Hara et al., (1991) isolated a new Antitumor antibiotic sapurimycin which is structurally related to but distinct from kapurimycins from a streptomyces sp. DO-116. The antibiotic was produced in a fermentation medium supplemented with high porus polymer resin which adsorbs antibiotic in the culture and resulted in an increase of titre. Sapurimycin was active against bacteria, particularly Gram positive bacteria and it exhibited antitumor activity

9 27 against leukemia P388 and sarcoma 180 in mice. Sapurimycin caused single strand breaks in supercoiled plasmid DNA in vitro. Takeuchi et al., (1991) isolated novel glycopeptide antibiotics helvecardins A and B from a strain of Psuedonocardia compounds sub ap. Helvitica. Suzuki et al., (1991) isolated an actinomycete strain Y l from beach sand collected at Chichijima, Ogasawara Island, Tokyo, Japan. It produced a new antibacterial antibiotic terazomine which exhibited antimicrobial activity against Gram positive bacteria and also exhibited strong cytotoxic activity against P388 leukemic cells. Selva et al., (1991) isolated a novel antibiotic GE-2270 A from the broth culture of Planobispora rosea. It was active against Gram positive bacteria and anaerobes. Tomita et al (1991) found five unusual actinomycetes, producing a family of antiviral antibiotics. They belong to seven compounds of fluvirucins A1, A2, B1, B2, B3, B4 & B5. All the strains had meso-2, 6-diamino-pimelic acid (meso-dap) in their cell walls. Four strains were identified as Actinomadura while the fifth one was Nocardioform actinomycete. Karwowski et al., (1991) isolated a new complex of spiroketal 24 membered macrolides, dunamycins from culture filtrates of two actinomycetes. They were identified as streptomyces diadtochromogenes strains-ab and AB1711j-452.The dunaimycin have both immunosuppressive and antimicrobial activities.

10 28 Hayakawa et al., (1991) described two methods for the isolation of the rare Actinomycetes viz. streptosporangium and Dactylosporangium from soil samples. The selective methods use the ability of both sporangiospores of streptosporangium and the globose bodies (aleurispores) of Dactylosporangium to with stand dry heating and treatment with benzethonium chloride. In addition, the differential antibiotic resistance of these actinomycetes is also used. The use of leuomycin and Dactylosporangia respectively from various field soils (vegetable, orchard, corn and rice paddy).the methods described above consistently achieved the highly selective isolation of Streptosporangia and Dactylosporangia, respectively, as each group accounted for more than 20%of the total number of colonies recovered. Tsunakawa et al., (1992) isolated a new actinomycete strain, Amycolaptosis orientalis No.Q427-8(ATCC53884) from a soil sample collected in Maharashtra state, India, which produced a complex of new antiviral antibiotics,the quatromicins. Structural studies suggested that they are a novel type of molecules unrelated to any known antibiotics. Each component of quatromicin exhibited antiviral activity against herpes simplex virus type I influenza virus type A and HIV. Tsunakawa et al., (1992) isolated new antiviral antibiotics, cycloviracins, (B1 and B2) from Kibdelosporangium albatum No.761-7(ATCC-55061). Cycloviracins showed potent antiviral activity against

11 29 herpes simplex virus type I and weak activity against Gram positive bacteria. Furumai et al., (1993) designed a screening system in search of benanomicin A producing actinomycetes from soil samples. 15 actinomycetes (mainly Actinomadura) producing red pigments and /or reverse growth were isolated from 140 soil samples collected in various countries. Of the 15 isolates, four isolates belonging to actinomycetes antibiotic. The Actinomadura sp. AB 1236 proved more useful in the production of BMS when fermented in a medium containing D-serine and D-cycloserine. Nishiyama et al., (1993) isolated a novel antitumor antibiotic, verucopeptin from the fermentation broth of Actinomadura verrucosospora Q886-2 which exhibited good cytotoxic activity against B16 melanoma. Laifu et al., (1993) isolated 39 strains of alkalophillic actinomycetes from saline alkali soils in Yunnan which include Nocardiopsis, saccharothrix, Micromonospora and Streptomyces. Naruse et al., (1993) isolated a new actinomycete strain Microtetraspora purvosata sub sp. kistane sub sp.nov.(atcc55076)from a soil sample collected near Krishna river in Andhra Pradesh state, India. The isolate was found to produce new antiviral antibiotics, designated as kistamicins A and B.These antibiotics have potent activity against influenza virus type A. Nair et al., (1994) isolated an antifungal antibiotic, gopalamicin from the cells of two actinomycetes MSV-625 and MSV 616, which is

12 30 structurally similar to salbomycin which are elaiophylin and active against pathogenic fungi. Holmalathi et al., (1994) isolated actinomycetes from 10 soil samples, The samples include three sediments of pulp mill effluent of polluted marsh pond and the rest 5 are soil samples from finish coniferous woodland. 32 isolates were selected after preliminary screenings which are active against bacteria and fungi.the majority of the isolates showing antifungal activity produce polyene type antibiotics. Steinberg et al., (1994) isolated new glycothiohexide antibiotics which are structurally related to nosiheptide from the culture broth of an actinomycete belonging to the genus Sebekia strain LL-14E 605. The strain was classified as Sebekia based on the presence of meso diaminopimelic acid and madurose sugar in the cell wall and the presence of pseudo sporangia enclosing the spores. The antibiotic Glycothiohexide exhibited excellent antibacterial activity against Gram positive bacteria particularly against methicillin resistant staph.aureus and vancomycin resistant Enterococcus faecalis with MICs in the range of 0.03 to 0.06 µg/ml Tsuchida et al., (1995) isolated a new structural class of antibiotics azicemins A(1) and B(2) from the fermentation broth of strain MJ 126-nf4, which was closely related to Amycolaptosis sulphurea. The antimicrobial activities of A(1) and A(2) are moderate against Gram positive bacteria and mycobacteria. These compounds

13 31 did not show any toxic sign in mice at a dose of 75.5 mg/kg when administered intravenously. Hayakawa et al., (1995) screened a variety of field soils by a new plate culture method in which water suspension of dry- heated (110C, 1 hour) soil was treated with 1.0% phenol and grown on fumic acid vitamin agar supplemented with kanamycin, josamycin,lysozyme and nalidixic acid. The method significantly eliminated bacteria and undesirable actinomycete contaminants from the isolation plates and resulted in the isolation of a rare actinomycete, Actinomodura viridis. Murata et al., (1995) characterized a new class of macrolide antibiotic aculeximycin having 30 memberd polyhydroxy macrocyclic lactone and five sugars from Streptosporangium albidum. Raytapadar and paul et al, (1995) screened 35 soil samples from 14 districts of west Bengal and isolated 327 actinomycetes. The isolates were screened for their antagonistic activities against bacteria and fungi. Of the 327 isolates, 77 isolates exhibited only antibacterial and antifungal activities. Russel et al., (1996) reported quinoxapetin A and B, which are novel chromodesipeptides from a Nocardiofrom actinomycete and they are potent inhibitors of HIV-1 and HIV-2 reverse transcriptase. Tanaka et al., (1997) isolated chloropeptins I and II which are gp 120-cd4 binding inhibitors from the mycelium of a soil actinomycete, streptomyces sp. WK Chloropeptin I is a novel compound while chloropeptin II was identified as complestain. Chloropeptin I has

14 32 synergistic activity with anti HIV- drugs such as zidovudine (AZT), didanosine (ddl) zalcitabne (ddc) and nevirapine. Saki et al., (1997) isolated a novel cyclic hexadedsipeptide antibiotic, GE3 from the fermentation broth of streptomyces sp. GE3.It exhibited potent cytotoxicity against human tumour cell lines. Matsumoto et al., (1997) reported a new structural class of antibiotics epoxyquinomicins A, B, C and D from the culture broth of strain MK F4 which was related to Amycolatopsis sulphurea. Igarashi et al., (1997) isolated a novel herbicidal and antifungal antibiotic, resormycin from the culture filtrate of a Streptomycete strain which was identified as Streptomyces platentsis MJ 953-DF5. Resormycin inhibited the growth of phytopathogenic fungi.