PERTANIKA JOURNAL OF TROPICAL AGRICULTURAL SCIENCE

Bacteria have produced many important secondary metabolites, especially in the pharmaceutical industry. However, the increase in the rediscovery rate of the known compound has been inconvenient to researchers and the pharmaceutical industry. Nevertheless, genome mining in bacteria has uncovered several cryptic metabolic pathways that may be key to discovering new secondary metabolites. The conventional laboratory environment, however, limits the metabolic pathways of microorganisms, making it impossible for secondary metabolites to be produced. As a result, researchers began using epigenetics to change the expression of the genes that code for secondary metabolites in microorganisms. Using epigenetics modifiers, secondary metabolite gene clusters are activated without altering the bacterial DNA sequence. This review article focuses on the different epigenetic changes and how they affect gene expression to activate the synthesis of secondary metabolites in bacteria.

• Akone, S. H., Pham, C.-D., Chen, H., Ola, A. R., Ntie-Kang, F., & Proksch, P. (2018). Epigenetic modification, co-culture and genomic methods for natural product discovery. Physical Sciences Reviews, 4(4), Article 20180118. https://doi.org/10.1515/psr-2018-0118

• Baral, B., Akhgari, A., & Metsä-Ketelä, M. (2018). Activation of microbial secondary metabolic pathways: Avenues and challenges. Synthetic and Systems Biotechnology, 3(3), 163-178. https://doi.org/10.1016/j.synbio.2018.09.001

• Belknap, K., Park, C., Barth, B., & Andam, C. (2020). Genome mining of biosynthetic and chemotherapeutic gene clusters in streptomyces bacteria. Scientific Reports, 10, Article 2003. https://doi.org/10.1038/s41598-020-58904-9

• Bind, S., Bind, S., Sharma, A. K., & Chaturvedi, P. (2022). Epigenetic modification: A key tool for secondary metabolite production in microorganisms. Frontiers in Microbiology, 13, Article 784109. https://doi.org/10.3389/fmicb.2022.784109

• Chakraborty, P. (2022). Gene cluster from plant to microbes: Their role in genome architecture, organism's development, specialised metabolism and drug discovery. Biochimie, 193, 1-15. https://doi.org/10.1016/j.biochi.2021.12.001

• Fernandez, M., Soliveri, J., Novella, I., Yebra, M., Barbés, C., & Sánchez, J. (1995). Effect of 5-azacytidine and sinefungin on streptomyces development. Gene, 157(1-2), 221-223. https://doi.org/10.1016/0378-1119(94)00672-F

• Fischer, N., Sechet, E., Friedman, R., Amiot, A., Sobhani, I., Nigro, G., Sansonetti, P. J., & Sperandio, B. (2016). Histone deacetylase inhibition enhances antimicrobial peptide but not inflammatory cytokine expression upon bacterial challenge. Proceedings of the National Academy of Sciences of the United States of America, 113(21), E2993-E3001. https://doi.org/10.1073/pnas.1605997113

• Gross, H., & Loper, J. E. (2009). Genomics of secondary metabolite production by pseudomonas spp. Natural Product Reports, 26(11), 1408. https://doi.org/10.1039/b817075b

• Jackson, S., Crossman, L., Almeida, E., Margassery, L., Kennedy, J., & Dobson, A. (2018). Diverse and abundant secondary metabolism biosynthetic gene clusters in the genomes of marine sponge derived streptomyces spp. isolates. Marine Drugs, 16(2), Article 67. https://doi.org/10.3390/md16020067

• Kim, H. J., & Bae, S. C. (2011). Histone deacetylase inhibitors: Molecular mechanisms of action and clinical trials as anticancer drugs. American Journal of Translational Research, 3(2), 166-179.

• Klaus, J., Coulon, P., Koirala, P., Seyedsayamdost, M., Déziel, E., & Chandler, J. (2020). Secondary metabolites from the Burkholderia pseudomallei complex: Structure, ecology, and evolution. Journal of Industrial Microbiology and Biotechnology, 47(9-10), 877-887. https://doi.org/10.1007/s10295-020-02317-0

• Kumar, J., Sharma, V. K., Singh, D. K., Mishra, A., Gond, S. K., Verma, S. K., Kumar, A., & Kharwar, R. N. (2016). Epigenetic activation of antibacterial property of an endophytic Streptomyces coelicolor strain AZRA 37 and identification of the induced protein using MALDI TOF MS/MS. PloS One, 11(2), Article e0147876. https://doi.org/10.1371/journal.pone.0147876

• Lauffer, B. E. L., Mintzer, R., Fong, R., Mukund, S., Tam, C., Zilberleyb, I., Flicke, B., Ritscher, A., Fedorowicz, G., Vallero, R., Ortwine, D. F., Gunzner, J., Modrusan, Z., Neumann, L., Koth, C. M., Lupardus, P. J., Kaminker, J. S., Heise, C. E., & Steiner, P. (2013). Histone deacetylase (HDAC) inhibitor kinetic rate constants correlate with cellular histone acetylation but not transcription and cell viability. Journal of Biological Chemistry, 288(37), 26926-26943. https://doi.org/10.1074/jbc.M113.490706

• Le Govic, Y., Papon, N., Le Gal, S., Bouchara, J., & Vandeputte, P. (2019). Non-ribosomal peptide synthetase gene clusters in the human pathogenic fungus Scedosporium apiospermum. Frontiers in Microbiology, 10, Article 2062. https://doi.org/10.3389/fmicb.2019.02062

• Lebedeva, J., Jukneviciute, G., Čepaitė, R., Vickackaite, V., Pranckutė, R., & Kuisiene, N. (2021). Genome mining and characterisation of biosynthetic gene clusters in two cave strains of Paenibacillus sp. Frontiers in Microbiology, 11, Article 612483. https://doi.org/10.3389/fmicb.2020.612483

• Lee, N., Hwang, S., Kim, J., Cho, S., Palsson, B., & Cho, B. K. (2020). Mini review: Genome mining approaches for the identification of secondary metabolite biosynthetic gene clusters in Streptomyces. Computational and Structural Biotechnology Journal, 18, 1548-1556. https://doi.org/10.1016/j.csbj.2020.06.024

• Li, G., Tian, Y., & Zhu, W. (2020). The roles of histone deacetylases and their inhibitors in cancer therapy. Frontiers in Cell and Developmental Biology, 8, Article 576946. https://doi.org/10.3389/fcell.2020.576946

• Li, J. W., & Vederas, J. C. (2009). Drug discovery and natural products: End of an era or an endless frontier? Science, 325(5937), 161-165. https://doi.org/10.1126/science.1168243

• Little, R. F., Samborskyy, M., & Leadlay, P. F. (2020). The biosynthetic pathway to tetromadurin (SF2487/A80577), a polyether tetronate antibiotic. PloS One, 15(9), Article e0239054. https://doi.org/10.1371/journal.pone.0239054

• Liu, Z., Zhao, Y., Huang, C., & Luo, Y. (2021). Recent advances in silent gene cluster activation in streptomyces, Frontiers in Bioengineering and Biotechnology, 9, Article 632230. https://doi.org/10.3389/fbioe.2021.632230

• Medema, M. H., Kottmann, R., Yilmaz, P., Cummings, M., Biggins, J. B., Blin, K., de Bruijn, I., Chooi, Y. H., Claesen, J., Coates, R. C., Cruz-Morales, P., Duddela, S., Düsterhus, S., Edwards, D. J., Fewer, D. P., Garg, N., Geiger, C., Gomez-Escribano, J. P., Greule, A., … & Glöckner, F. O. (2015). Minimum information about a biosynthetic gene cluster. Nature Chemical Biology, 11(9), 625-631. https://doi.org/10.1038/nchembio.1890

• Militello, K. T., Simon, R. D., Mandarano, A. H., DiNatale, A., Hennick, S. M., Lazatin, J. C., & Cantatore, S. (2016). 5-azacytidine induces transcriptome changes in Escherichia coli via DNA methylation-dependent and DNA methylation-independent mechanisms. BMC Microbiology, 16, Article 130. https://doi.org/10.1186/s12866-016-0741-4

• Moore, J. M., Bradshaw, E., Seipke, R. F., Hutchings, M. I., & McArthur, M. (2012). Use and discovery of chemical elicitors that stimulate biosynthetic gene clusters in Streptomyces bacteria. Methods in Enzymology, 517, 367-385. https://doi.org/10.1016/B978-0-12-404634-4.00018-8

• Murray, C., Ikuta, K., Sharara, F., Swetschinski, L., Robles Aguilar, G., & Gray, A., Gray, A., Han, C., Bisignano, C., Rao, P., Wool, E., Johnson, S. C., Browne, A. J., Chipeta, M. G., Fell, F., Hackett, S., Haines-Woodhouse, G. Hamadani, B. H. K., Kumaran, E. A. P., McManigal, B., ... & Naghavi, M. (2022). Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. The Lancet, 399(10325), 629-655. https://doi.org/10.1016/S0140-6736(21)02724-0

• Okada, B. K., & Seyedsayamdost, M. R. (2017). Antibiotic dialogues: Induction of silent biosynthetic gene clusters by exogenous small molecules. FEMS Microbiology Reviews, 41(1), 19-33. https://doi.org/10.1093/femsre/fuw035

• Ou, Y., Zhang, Q., Tang, Y., Lu, Z., Lu, X., Zhou, X., & Liu, C. (2018). DNA methylation enzyme inhibitor RG108 suppresses the radioresistance of esophageal cancer. Oncology Reports, 39(3), 993-1002. https://doi.org/10.3892/or.2018.6210

• Pahalagedara, A. S. N. W., Flint, S., Palmer, J., Brightwell, G., & Gupta, T. B. (2020). Antimicrobial production by strictly anaerobic clostridium spp. International Journal of Antimicrobial Agents, 55(5), Article 105910. https://doi.org/10.1016/j.ijantimicag.2020.105910

• Pettit, R. (2011). Small-molecule elicitation of microbial secondary metabolites. Microbial Biotechnology, 4(4), 471-478. https://doi.org/10.1111/j.1751-7915.2010.00196.x

• Pfannenstiel, B. T., & Keller, N. P. (2019). On top of biosynthetic gene clusters: How epigenetic machinery influences secondary metabolism in fungi. Biotechnology Advances, 37(6), Article 107345. https://doi.org/10.1016/j.biotechadv.2019.02.001

• Pillay, L. C., Nekati, L., Makhwitine, P. J., & Ndlovu, S. I. (2022). Epigenetic activation of silent biosynthetic gene clusters in endophytic fungi using small molecular modifiers. Frontiers in Microbiology, 13, Article 815008. https://doi.org/10.3389/fmicb.2022.815008

• Poças-Fonseca, M. J., Cabral, C. G., & Manfrão-Netto J. H. C. (2020). Epigenetic manipulation of filamentous fungi for biotechnological applications: A systematic review. Biotechnology Letters, 42, 885-904. https://doi.org/10.1007/s10529-020-02871-8

• Ramesha, K., Mohana, N., Nuthan, B., Rakshith, D., & Satish, S. (2018). Epigenetic modulations of mycoendophytes for novel bioactive molecules. Biocatalysis and Agricultural Biotechnology, 16, 663-668. https://doi.org/10.1016/j.bcab.2018.09.025

• Rutledge, P. J., & Challis, G. L. (2015). Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nature Reviews Microbiology, 13, 509-523. https://doi.org/10.1038/nrmicro3496

• Scherlach, K., & Hertweck, C. (2021). Mining and unearthing hidden biosynthetic potential. Nature Communication, 12, Article 3864. https://doi.org/10.1038/s41467-021-24133-5

• Schumacher, J. D. (2014). Epigenetic modification and analysis of natural product gene clusters to enhance drug discovery from bacteria (Publication no. 309). [Master’s thesis]. University of Rhode Island, USA. https://doi.org/10.23860/thesis-schumacher-justin-2014

• Shah, A. M., Shakeel-U-Rehman, Hussain, A., Mushtaq, S., Rather, M. A., Shah, A., Ahmad, Z., Khan, I. A., Bhat, K. A., & Hassan, Q. P. (2017). Antimicrobial investigation of selected soil actinomycetes isolated from unexplored regions of Kashmir Himalayas, India. Microbial Pathogenesis, 110, 93-99. https://doi.org/10.1016/j.micpath.2017.06.017

• Smanski, M., Zhou, H., Claesen, J., Shen, B., Fischbach, M., & Voigt, C. (2016). Synthetic biology to access and expand nature's chemical diversity. Nature Reviews Microbiology, 14, 135-149. https://doi.org/10.1038/nrmicro.2015.24

• Strauss, J., & Reyes-Dominguez, Y. (2011). Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genetics and Biology, 48(1), 62-69. https://doi.org/10.1016/j.fgb.2010.07.009

• Tanaka, Y., Kasahara, K., Hirose, Y., Murakami, K., Kugimiya, R., & Ochi, K. (2013). Activation and products of the cryptic secondary metabolite biosynthetic gene clusters by rifampin resistance (rpoB) mutations in actinomycetes. Journal of Bacteriology, 195(13), 2959-2970. https://doi.org/10.1128/JB.00147-13

• Trautman, E. P., & Crawford, J. M. (2016). Linking biosynthetic gene clusters to their metabolites via pathway-targeted molecular networking. Current Topics in Medicinal Chemistry, 16(15), 1705-1716. https://doi.org/10.2174/1568026616666151012111046

• Vandenbussche, I., Sass, A., Pinto-Carbó, M., Mannweiler, O., Eberl, L., & Coenye, T. (2020). DNA methylation epigenetically regulates gene expression in Burkholderia cenocepacia and controls biofilm formation, cell aggregation, and motility. Molecular Biolody and Physiology, 5(4), Article e00455-20. https://doi.org/10.1128/mSphere.00455-20

• Wang, B., Waters, A. L., Sims, J. W., Fullmer, A., Ellison, S., & Hamann, M. T. (2013). Complex marine natural products as potential epigenetic and production regulators of antibiotics from a marine Pseudomonas aeruginosa. Microbial Ecology, 65, 1068-1075. https://doi.org/10.1007/s00248-013-0213-4

• Weinhold B. (2006). Epigenetics: The science of change. Environmental Health Perspectives, 114(3), A160-A167. https://doi.org/10.1289/ehp.114-a160

• Xue, Y., & Acar, M. (2018). Mechanisms for the epigenetic inheritance of stress response in single cells. Current Genetics, 64, 1221-1228. https://doi.org/10.1007/s00294-018-0849-1

• Yang, K., Tian, J., & Keller, N. P. (2022). Post-translational modifications drive secondary metabolite biosynthesis in aspergillus: A review. Environmental Microbiology, 24(7), 2857-2881. https://doi.org/10.1111/1462-2920.16034

• Zhang, Y., Chen, M., Bruner, S., & Ding, Y. (2018). Heterologous production of microbial ribosomally synthesised and post-translationally modified peptides. Frontiers in Microbiology, 9, Article 1801. https://doi.org/10.3389/fmicb.2018.01801