Sains Malaysiana 48(3)(2019): 543–553

http://dx.doi.org/10.17576/jsm-2019-4803-06

Fenazin sebagai Potensi Antibiotik Baru daripada Streptomyces kebangsaanensis

(Fenazin as Potential New Antibiotics from Streptomyces kebangsaanensis)

JUWAIRIAH REMALI¹, NORAZIAH MOHAMAD ZIN^2*, CHYAN LEONG NG³, WAN M. AIZAT³ & JOHN J.L TIONG⁴

¹Pusat Pengajian Biosains dan Bioteknologi, Fakulti Sains dan Teknologi, Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor Darul Ehsan, Malaysia

²Pusat Penuaan Sihat dan Kesejahteraan (HCARE), Fakulti Sains Kesihatan, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, 50300 Kuala Lumpur, Federal Territory, Malaysia

³Institut Biologi Sistem (INBIOSIS), Universiti Kebangsaan Malaysia, 43600 UKM Bangi, Selangor Darul Ehsan, Malaysia

⁴Pusat Pengajian Farmasi, Universiti Taylor, No. 1, Jalan Taylor’s, 47500 Subang Jaya, Selangor Darul Ehsan, Malaysia

Received: 31 March 2018/Accepted: 15 November 2018

ABSTRAK

Fenazin merupakan metabolit sekunder yang biasanya disintesis secara semula jadi oleh Pseudomonas dan Streptomyces. Ia merupakan sebatian heterosiklik yang mempunyai sebatian bernitrogen pada struktur teras cecincin. Kajian mengenai antibiotik ini telah bermula seawal abad ke-19 lagi dan ternyata menjadi calon dadah yang berpotensi tinggi dalam dunia perubatan. Sehingga kini, lebih daripada 100 jenis fenazin telah diterokai daripada sumber semula jadi dan boleh bertindak sebagai antibakteria, antikanser, antivirus, antitumor serta antiparasit. Setakat ini, kajian biosintesis fenazin yang telah dijalankan terhadap Pseudomonas dan Streptomyces telah mendedahkan gen yang bertanggungjawab dalam tapak jalan biosintesis fenazin, namun begitu, gen khusus yang terlibat dalam penghasilan terbitan fenazin yang kompleks masih dalam hipotesis. Dalam ulasan ini, kami membincangkan kepentingan fenazin serta pemahaman terkini tentang tapak jalan biosintesis fenazin yang berjaya diterokai di dalam Streptomyces kebangsaanensis.

Kata kunci: Antibiotik; biosintesis; fenazin; Streptomyces kebangsaanensis

ABSTRACT

Phenazine is a secondary metabolite that is naturally synthesized by Pseudomonas and Streptomyces. It is a heterocyclic compound that has nitrogen group at the core structure of the ring. The study of antibiotics has begun since 19th century and turned out to be a highly potential drug in a medical world. To date, more than 100 types of phenazines have been discovered from natural sources and acted as antibacterial, anticancer, antiviral, antitumor and antiparasites. To date, the study of phenazine biosynthesis was carried out on Pseudomonas and Streptomyces has showed the genes responsible in the pathway of phenazine biosynthesis but the specific genes involved in the production of complex phenazine derivatives are still hypothetical. In this review, we discuss the importance of phenazine as well as the latest understanding of phenazine biosynthesis pathways that have been successful discovered in Streptomyces kebangsaanensis.

Keywords: Antibiotics; biosynthesis; phenazine; Streptomyces kebangsaanensis

REFERENCES

Abdelfattah, M.S., Ishikawa, N., Karmakar, U.K., Yamaku, K. & Ishibashi, M. 2016. New phenazine analogues from Streptomyces sp. IFM 11694 with TRAIL resistance-overcoming activities. Journal of Antibiotics 69(6): 446-450.

Abdelfattah, M.S., Toume, K. & Ishibashi, M. 2011. Isolation and structure elucidation of izuminosides A-C: A rare phenazine glycosides from Streptomyces sp. IFM 11260. Journal of Antibiotics 64(3): 271-275.

Abken, H.J., Tietze, M., Brodersen, J., Bäumer, S., Beifuss, U. & Deppenmeier, U. 1998. Isolation and characterization of methanophenazine and function of phenazines in membrane-bound electron transport of Methanosarcina mazei Gö1. Journal of Bacteriology 180(8): 2027-2032.

Arbiser, J.L. & Moschella, S.L. 1995. Clofazimine: A review of its medical uses and mechanisms of action. Journal of the American Academy of Dermatology 32(2): 241-247.

Asano, K., Takahashi, K., Tomita, F. & Kawamoto, I. 1986. DC- 86-M, a novel antitumor antibiotic. I. Taxonomy of producing organism and fermentation. The Journal of Antibiotics 39(5): 619-623.

Blankenfeldt W. 2013. The biosynthesis of phenazines. Dlm. Microbial Phenazines, disunting oleh Chincholkar, S. & Thomashow, L. Springer, Berlin, Heidelberg. hlm. 1-17.

Blankenfeldt, W., Kuzin, A.P., Skarina, T., Korniyenko, Y., Tong, L., Bayer, P., Janning, P., Thomashow, L.S. & Mavrodi, D.V. 2004. Structure and function of the phenazine biosynthetic protein PhzF from Pseudomonas fluorescens. Proceedings of the National Academy of Sciences of the United States of America 101(47): 16431-16436.

Brisbane, P.G., Janik, L.J., Tate, M. & Warren, R. 1987. Revised structure for the phenazine antibiotic from Pseudomonas fluorescens 2-79 (NRRL B-15132). Antimicrobial Agents and Chemotherapy 31(12): 1967-1971.

Cha, J.W., Lee, S.Il, Kim, M.C., Thida, M., Lee, J.W., Park, J.S. & Kwon, H.C. 2015. Pontemazines A and B, phenazine derivatives containing a methylamine linkage from Streptomyces sp. UT1123 and their protective effect to HT-22 neuronal cells. Bioorganic and Medicinal Chemistry Letters 25(22): 5083-5086.

Delaney, S.M., Mavrodi, D.V., Bonsall, R.F. & Thomashow, L.S. 2001. phzO, a gen for biosynthesis of 2-hydroxylated phenazine compounds in Pseudomonas aureofaciens 30-84. Journal of Bacteriology 183(1): 318-327.

Dietrich, L.E., Price-Whelan, A., Petersen, A., Whiteley, M. & Newman, D.K. 2006. The phenazine pyocyanin is a terminal signalling factor in the quorum sensing network of Pseudomonas aeruginosa. Molecular Microbiology 61(5): 1308-1321.

Ding, Z.G., Li, M.G., Ren, J., Zhao, J.Y., Huang, R., Wang, Q.Z., Cui, X.L., Zhu, H.J. & Wen, M.L. 2011. Phenazinolins A-E: Novel diphenazines from a tin mine tailings-derived Streptomyces species. Organic & Biomolecular Chemistry 9(8): 2771-2776.

Emerson, J., Rosenfeld, M., McNamara, S., Ramsey, B. & Gibson, R.L. 2002. Pseudomonas aeruginosa and other predictors of mortality and morbidity in young children with cystic fibrosis. Pediatric Pulmonology 34(2): 91-100.

Fitzpatrick, D.A. 2009. Lines of evidence for horizontal gene transfer of a phenazine producing operon into multiple bacterial species. Journal of Molecular Evolution 68(2): 171-185.

Fordos, M. 1860. Recherches sur la matière colorante des suppurations bleues: Pyocyanine. CR Acad. Sci. 51: 215-217.

Gebhardt, K., Schimana, J., Krastel, P., Dettner, K., Rheinheimer, J., Zeeck, A. & Fiedler, H.P. 2002. Endophenazines AD, new phenazine antibiotics from the arthropod associated endosymbiont Streptomyces anulatus. I. Taxonomy, fermentation, isolation and biological activities. The Journal of Antibiotics 55(9): 794-800.

Geiger, A., Keller-Schierlein, W., Brandl, M. & Zähner, H. 1988. Metabolites of microorganisms. 247. Phenazines from Streptomyces antibioticus, strain Tu 2706. The Journal of Antibiotics 41(11): 1542-1551.

Gessard, C. 1882. Sur les colorations bleue et verte des linges a pansements. Compt. Rend. Acad. Sci. 94: 536-568.

Giddens, S.R., Houliston, G.J. & Mahanty, H.K. 2003. The influence of antibiotic production and pre-emptive colonization on the population dynamics of Pantoea agglomerans (Erwinia herbicola) Eh1087 and Erwinia amylovora in planta. Environmental Microbiology 5(10): 1016-1021.

Giddens, S.R., Feng, Y. & Mahanty, H.K. 2002. Characterization of a novel phenazine antibiotic gen cluster in Erwinia herbicola Eh1087. Molecular Microbiology 45(3): 769-783.

Guttenberger, N., Blankenfeldt, W. & Breinbauer, R. 2017. Recent developments in the isolation, biological function, biosynthesis, and synthesis of phenazine natural products. Bioorganic and Medicinal Chemistry 25(22): 6149-6166.

Hassan, H.M. & Fridovich, I. 1980. Mechanism of the antibiotic action pyocyanine. Journal of Bacteriology 141(1): 156-163.

Hernandez, M.E., Kappler, A. & Newman, D.K. 2004. Phenazines and other redox-active antibiotics promote microbial mineral reduction. Applied and Environmental Microbiology 70(2): 921-928.

Hollstein, U. & Van Gemert Jr., R.J. 1971. Interaction of phenazines with polydeoxyribonucleotides. Biochemistry 10(3): 497-504.

Hollstein, U., Mock, D.L., Sibbitt, R.R., Roisch, U. & Lingens, F. 1978. Incorporation of shikimic acid into iodinin. Tetrahedron Letters 19(33): 2987-2990.

Jayatilake, G.S., Thornton, M.P., Leonard, A.C., Grimwade, J.E. & Baker, B.J. 1996. Metabolites from an Antarctic sponge-associated bacterium, Pseudomonas aeruginosa. Journal of Natural Products 59(3): 293-296.

Johnson, L.E. & Dietz, A. 1969. Lomofungin, a new antibiotic produced by Streptomyces lomondensis sp. n. Applied Microbiology 17(5): 755-759.

Kearns, L. & Hale, C. 1996. Partial characterization of an inhibitory strain of Erwinia herbicola with potential as a biocontrol agent for Erwinia amylovora, the fire blight pathogen. Journal of Applied Bacteriology 81(4): 369-374.

Kennedy, R.K., Naik, P.R., Veena, V., Lakshmi, B.S., Lakshmi, P., Krishna, R. & Sakthivel, N. 2015. 5-Methyl phenazine- 1-carboxylic acid: A novel bioactive metabolite by a rhizosphere soil bacterium that exhibits potent antimicrobial and anticancer activities. Chemico-Biological Interactions 231: 71-82.

Kerr, J. 2000. Phenazine pigments; Antibiotics and virulence factors. Infectious Disease Review 2(4): 184-194.

Kim, W.G., Ryoo, I.J., Yun, B.S., Shin-Ya, K., Seto, H. & Yoo, I.D. 1997. New diphenazines with neuronal cell protecting activity, phenazostatins A and B, produced by Streptomyces sp. The Journal of Antibiotics 50(9): 715-721.

Kitahara, M. 1982. Saphenamycin, a novel antibiotic from a strain of Streptomyces. Journal of Antibiotics 35(10): 1412-1414.

Krastel, P., Zeeck, A., Gebhardt, K., Fiedler, H.P. & Rheinheimer, J. 2002. Endophenazines AD, new phenazine antibiotics from the athropod associated endosymbiont Streptomyces anulatus II. Structure elucidation. The Journal of Antibiotics 55(9): 801-806.

Kondratyuk, T.P., Park, E.J., Yu, R., van Breemen, R.B., Asolkar, R.N., Murphy, B.T., Fenical, W. & Pezzuto, J.M. 2012. Novel marine phenazines as potential cancer chemopreventive and anti-inflammatory agents. Marine Drugs 10(12): 451-464.

Lau, G.W., Hassett, D.J., Ran, H. & Kong, F. 2004a. The role of pyocyanin in Pseudomonas aeruginosa infection. Trends in Molecular Medicine 10(12): 599-606.

Lau, G.W., Ran, H., Kong, F., Hassett, D.J. & Mavrodi, D. 2004b. Pseudomonas aeruginosa pyocyanin is critical for lung infection in mice. Infection and Immunity 72(7): 4275-4278.

Laursen, J.B. & Nielsen, J. 2004. Phenazine natural products: Biosynthesis, synthetic analogues, and biological activity. Chemical Reviews 104(3): 1663-1686.

Ledderhose, G. 1888. Ueber den blauen Eiter. Langenbecks Arch Klin Chir Ver Dtsch Z Chir 28: 201-230.

Levitch, M.E. & Rietz, P. 1966. The isolation and characterization of 2-hydroxyphenazine from Pseudomonas aureofaciens. Biochemistry 5(2): 689-692.

Levitch, M. & Stadtman, E. 1964. A study of the biosynthesis of phenazine-1-carboxylic acid. Archives of Biochemistry and Biophysics 106: 194-199.

Mavrodi, D.V., Parejko, J.A., Mavrodi, O.V., Kwak, Y.S., Weller, D.M., Blankenfeldt, W. & Thomashow, L.S. 2013. Recent insights into the diversity, frequency and ecological roles of phenazines in fluorescent Pseudomonas spp. Environmental Microbiology 15(3): 675-686.

Mavrodi, D.V., Peever, T.L., Mavrodi, O.V., Parejko, J.A., Raaijmakers, J.M., Lemanceau, P., Mazurier, S., Heide, L., Blankenfeldt, W. & Weller, D.M. 2010. Diversity and evolution of the phenazine biosynthesis pathway. Applied and Environmental Microbiology 76(3): 866-879.

Mavrodi, D.V., Blankenfeldt, W. & Thomashow, L.S. 2006. Phenazine compounds in fluorescent Pseudomonas sp. biosynthesis and regulation. Annual Review Phytopathology 44: 417-445.

Mavrodi, D.V., Bonsall, R.F., Delaney, S.M., Soule, M.J., Phillips, G. & Thomashow, L.S. 2001. Functional analysis of gens for biosynthesis of pyocyanin and phenazine-1- carboxamide from Pseudomonas aeruginosa PAO1. Journal of Bacteriology 183(21): 6454-6465.

McDonald, M., Mavrodi, D.V., Thomashow, L.S. & Floss, H.G. 2001. Phenazine biosynthesis in Pseudomonas fluorescens: Branchpoint from the primary shikimate biosynthetic pathway and role of phenazine-1, 6-dicarboxylic acid. Journal of the American Chemical Society 123(38): 9459-9460.

Mentel, M., Ahuja, E.G., Mavrodi, D.V., Breinbauer, R., Thomashow, L.S. & Blankenfeldt, W. 2009. Of two make one: The biosynthesis of phenazines. Chembiochem. 10(14): 2295-2304.

Parsons, J.F., Song, F., Parsons, L., Calabrese, K., Eisenstein, E. & Ladner, J.E. 2004a. Structure and function of the phenazine biosynthesis protein PhzF from Pseudomonas fluorescens 2-79. Biochemistry 43(39): 12427-12435.

Parsons, J.F., Calabrese, K., Eisenstein, E. & Ladner, J.E. 2004b. Structure of the phenazine biosynthesis enzyme PhzG. Acta Crystallographica Section D: Biological Crystallography 60(11): 2110-2113.

Pierson III, L.S. & Pierson, E.A. 2010. Metabolism and function of phenazines in bacteria: Impacts on the behavior of bacteria in the environment and biotechnological processes. Applied Microbiology and Biotechnology 86(6): 1659-1670.

Pierson, L.S., Gaffney, T., Lam, S. & Gong, F. 1995. Molecular analysis of gens encoding phenazine biosynthesis in the biological control bacterium Pseudomonas aureofaciens 30- 84. FEMS Microbiology Letters 134(2-3): 299-307.

Podojil, M. & Gerber, N.N. 1967. The biosynthesis of 1, 6-phenazinediol 5, 10-dioxide (Iodinin) by Brevibacterium iodinum. Biochemistry 6(9): 2701-2705.

Recinos, D.A., Sekedat, M.D., Hernandez, A., Cohen, T.S., Sakhtah, H., Prince, A.S., Price-Whelan, A. & Dietrich, L.E. 2012. Redundant phenazine operons in Pseudomonas aeruginosa exhibit environment-dependent expression and differential roles in pathogenicity. Proceedings of the National Academy of Sciences 109(47): 19420-19425.

Reddy, V.M., O’Sullivan, J.F. & Gangadharam, P.R. 1999. Antimycobacterial activities of riminophenazines. Journal of Antimicrobial Chemotherapy 43(5): 615-623.

Remali, J., Sarmin, N.I.M., Ng, C.L., Tiong, J.J.L., Aizat, W.M., Keong, L.K. & Zin, N.M. 2017b. Genomic characterization of a new endophytic Streptomyces kebangsaanensis identifies biosynthetic pathway gene clusters for novel phenazine antibiotic production. Peer J. 5: e3738.

Römer, A. & Herbert, R. 1982. Further observations on the source of nitrogen in phenazine biosynthesis. Z. Naturforsch., Ser. C. 37(11): 1070-1074.

Sarmin, N.I.M., Tan, G.Y.A., Franco, C.M., Edrada-Ebel, R., Latip, J. & Zin, N.M. 2013. Streptomyces kebangsaanensis sp. nov., an endophytic actinomycete isolated from an ethnomedicinal plant, which produces phenazine-1- carboxylic acid. International Journal of Systematic and Evolutionary Microbiology 63(Pt 10): 3733-3738.

Schoental, R. 1941. The nature of the antibacterial agents present in Pseudomonas pyocyanea cultures. British Journal of Experimental Pathology 22(3): 137-147.

Schroeter, J. 1872. Ueber einige durch Bacterien gebildete Pigmente. Beiträge zur Biologie der Pflanzen 1: 109-126.

Selengut, J.D. & Haft, D.H. 2010. Unexpected abundance of coenzyme F420-dependent enzymes in Mycobacterium tuberculosis and other actinobacteria. Journal of Bacteriology 192(21): 5788-5798.

Smirnov, V.V. & Kiprianova, E.A. 1990. Bacteria of Pseudomonas genus. Kiev, Ukraine: Naukova Dumka. hlm. 100-111.

Spicer, J.A., Gamage, S.A., Rewcastle, G.W., Finlay, G.J., Bridewell, D.J., Baguley, B.C. & Denny, W.A. 2000. Bis (phenazine-1-carboxamides): Structure-activity relationships for a new class of dual topoisomerase I/II-directed anticancer drugs. Journal of Medicinal Chemistry 43(7): 1350-1358.

Stewart, A.J., Mistry, P., Dangerfield, W., Bootle, D., Baker, M., Kofler, B., Okiji, S., Baguley, B.C., Denny, W.A. & Charlton, P.A. 2001. Antitumor activity of XR5944, a novel and potent topoisomerase poison. Anti-cancer Drugs 12(4): 359-367.

Cholo, C.M., Steel, H.C., Fourie, P.B., Germishuizen, W.A., Anderson, R. 2011. Clofazimine: Current status and future prospects. Journal of Antimicrobial Chemotherapy 67(2): 290-298.

Takahashi, I., Takahashi, K.I., Ichimura, M., Morimoto, M., Asano, K., Kawamoto, I., Tomita, F. & Nakano, H. 1988. Duocarmycin A, a new antitumor antibiotic from Streptomyces. The Journal of Antibiotics 41(12): 1915-1917.

Thomashow, L.S. & Weller, D.M. 1988. Role of a phenazine antibiotic from Pseudomonas fluorescens in biological control of Gaeumannomyces graminis var. tritici. Journal of Bacteriology 170(8): 3499-3508.

Thomashow, L.S., Weller, D.M., Bonsall, R.F. & Pierson, L.S. 1990. Production of the antibiotic phenazine-1-carboxylic acid by fluorescent Pseudomonas species in the rhizosphere of wheat. Applied and Environmental Microbiology 56(4): 908-912.

Turner, J.M. & Messenger, A.J. 1986. Occurrence, biochemistry and physiology of phenazine pigment production. Advances in Microbial Physiology 27: 211-275.

Van’t Land, C.W., Mocek, U. & Floss, H.G. 1993. Biosynthesis of the phenazine antibiotiks, the saphenamycins and esmeraldins, in Streptomyces antibioticus. The Journal of Organic Chemistry 58(24): 6576-6582.

Wang, Y., Luo, Q., Zhang, X. & Wang, W. 2011. Isolation and purification of a modified phenazine, griseoluteic acid, produced by Streptomyces griseoluteus P510. Research in Microbiology 162(3): 311-319.

Woeng, C.A.T.F., Bloemberg, G.V., van der Bij, A.J., van der Drift, K.M., Schripsema, J., Kroon, B., Scheffer, R.J., Keel, C., Bakker, P.A. & Tichy, H.V. 1998. Biocontrol by phenazine-1-carboxamide-producing Pseudomonas chlororaphis PCL1391 of tomato root rot caused by Fusarium oxysporum f. sp. radicis-lycopersici. Molecular Plant- Microbe Interactions 11(11): 1069-1077.

Wu, C., Van Wezel, G.P. & Hae Choi, Y. 2015. Identification of novel endophenaside antibiotics produced by Kitasatospora sp. MBT66. Journal of Antibiotics 68(7): 445-452.

Yun, B.S., Ryoo, I.J., Kim, W.G., Kim, J.P., Koshino, H., Scto, H. & Yoo, I.D. 1996. Structures of phenazostatins A and B, neuronal cell protecting substances of microbial origin. Tetrahedron Letters 37(47): 8529-8530.

*Corresponding author; email: noraziah.zin@ukm.edu.my