Abstract
Streptomyces is one of the most versatile genera for biotechnological applications, widely employed as platform in the production of drugs. Although streptomycetes have a complex life cycle and metabolism that would need multidisciplinary approaches, review papers have generally reported only studies on single aspects like the isolation of new strains and metabolites, morphology investigations, and genetic or metabolic studies. Besides, even if streptomycetes are extensively used in industry, very few review papers have focused their attention on the technical aspects of biotechnological processes of drug production and bioconversion and on the key parameters that have to be set up. This mini-review extensively illustrates the most innovative developments and progresses in biotechnological production and bioconversion processes of antibiotics, immunosuppressant, anticancer, steroidal drugs, and anthelmintic agents by streptomycetes, focusing on the process development aspects, describing the different approaches and technologies used in order to improve the production yields. The influence of nutrients and oxygen on streptomycetes metabolism, new fed-batch fermentation strategies, innovative precursor supplementation approaches, and specific bioreactor design as well as biotechnological strategies coupled with metabolic engineering and genetic tools for strain improvement is described. The use of whole, free, and immobilized cells on unusual supports was also reported for bioconversion processes of drugs. The most outstanding thirty investigations published in the last 8 years are here reported while future trends and perspectives of biotechnological research in the field have been illustrated.
Key points
• Updated Streptomyces biotechnological processes for drug production are reported.
• Innovative approaches for Streptomyces-based biotransformation of drugs are reviewed.
• News about fermentation and genome systems to enhance secondary metabolite production.
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References
Anderson AS, Wellington EM (2001) The taxonomy of Streptomyces and related genera. Int J Syst Evol Microbiol 51:797–814. https://doi.org/10.1099/00207713-51-3-797
Anteneh YS, Franco CMM (2019) Whole cell Actinobacteria as biocatalysts. Front Microbiol 10. https://doi.org/10.3389/fmicb.2019.00077
Argoudelis AD, Coats JH (1969) Microbial transformation of antibiotics. II. Phosphorylation of lincomycin by Streptomyces species. J Antibiot 22:341–343. https://doi.org/10.7164/antibiotics.22.341
Argoudelis AD, Coats JH (1971) Microbial transformation of antibiotics. VI. Acylation of chloramphenicol by Streptomyces coelicolor. J Antibiot 24:206–208. https://doi.org/10.7164/antibiotics.24.206
Atta FM, Zohri AA (1995) Transformation reactions of progesterone by different species of Streptomyces. J Basic Microbiol 35:1–7. https://doi.org/10.1002/jobm.3620350102
Berrie JR, Williams RAD, Smith KE (1999) Microbial transformations of steroids-XI. Progesterone transformation by Streptomyces roseochromogenes–purification and characterisation of the 16α-hydroxylase system. J Steroid Biochem 71:153–165. https://doi.org/10.1016/S0960-0760(99)00132-6
Bitterwolf P, Ott F, Rabe KS, Niemeyer CM (2019) Imine reductase based all-enzyme hydrogel with intrinsic cofactor regeneration for flow biocatalysis. Micromachines 10. https://doi.org/10.3390/mi10110783
Brautaset T, Bruheim P, Sletta H, Hagen L, Ellingsen TE, Strøm AR, Valla S, Zotchev SB (2002) Hexaene derivatives of nystatin produced as a result of an induced rearrangement within the nysC polyketide synthase gene in S. noursei ATCC 11455. Chem Biol 9:367–373. https://doi.org/10.1016/s1074-5521(02)00108-4
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM (2020) The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res 178:104787. https://doi.org/10.1016/j.antiviral.2020.104787
Chakravarty I, Kundu S (2016) Improved production of daptomycin in an airlift bioreactor by morphologically modified and immobilized cells of Streptomyces roseosporus. AMB Express 6:101. https://doi.org/10.1186/s13568-016-0274-0
Chater KF (2016) Recent advances in understanding Streptomyces. F1000Res 5:2795. https://doi.org/10.12688/f1000research.9534.1
Chin HS, Sim J, Sim TS (2001) Mutation of N304 to leucine in Streptomyces clavuligerus deacetoxycephalosporin C synthase creates an enzyme with increased penicillin analogue conversion. Biochem Biophys Res Commun 287:507–513. https://doi.org/10.1006/bbrc.2001.5552
Coze F, Gilard F, Tcherkez G, Virolle M-J, Guyonvarch A (2013) Carbon-flux distribution within Streptomyces coelicolor metabolism: a comparison between the actinorhodin-producing strain M145 and its non-producing derivative M1146. PLoS One 8:e84151. https://doi.org/10.1371/journal.pone.0084151
Cui P, Zhong W, Qin Y, Tao F, Wang W, Zhan J (2020) Characterization of two new aromatic amino acid lyases from Actinomycetes for highly efficient production of p-coumaric acid. Bioprocess Biosyst Eng 43:1287–1298. https://doi.org/10.1007/s00449-020-02325-5
de Carvalho CCCR (2016) Whole cell biocatalysts: essential workers from nature to the industry. Microb Biotechnol 10:250–263. https://doi.org/10.1111/1751-7915.12363
de Lima Procópio RE, da Silva IR, Martins MK, de Azevedo JL, de Araújo JM (2012) Antibiotics produced by Streptomyces. Braz J Infect Dis 16:466–471. https://doi.org/10.1016/j.bjid.2012.08.014
Demain AL (2006) From natural products discovery to commercialization: a success story. J Ind Microbiol Biotechnol 33:486–495. https://doi.org/10.1007/s10295-005-0076-x
Demain AL, Báez-Vásquez MA (2000) Immobilized Streptomyces clavuligerus NP1 cells for biotransformation of penicillin G into deacetoxycephalosporin G. Appl Biochem Biotechnol 87:135–140. https://doi.org/10.1385/ABAB:87:2:135
Deng Q, Xiao L, Liu Y, Zhang L, Deng Z, Zhao C (2019) Streptomyces avermitilis industrial strain as cell factory for Ivermectin B1a production. Synth Syst Biotechnol 4:34–39. https://doi.org/10.1016/j.synbio.2018.12.003
Diana M, Quílez J, Rafecas M (2014) Gamma-aminobutyric acid as a bioactive compound in foods: a review. J Funct Foods 10:407–420. https://doi.org/10.1016/j.jff.2014.07.004
Dickens ML, Strohl WR (1996) Isolation and characterization of a gene from Streptomyces sp. strain C5 that confers the ability to convert daunomycin to doxorubicin on Streptomyces lividans TK24. J Bacteriol 178:3389–3395. https://doi.org/10.1128/jb.178.11.3389-3395.1996
Dlugoński J, Sedlaczek L (1981) Regulation of steroid 16α-hydroxylation in Streptomyces olivoviridis. Z Allg Mikrobiol 21:499–506. https://doi.org/10.1002/jobm.3630210703
Du W, Huang D, Xia M, Wen J, Huang M (2014) Improved FK506 production by the precursors and product-tolerant mutant of Streptomyces tsukubaensis based on genome shuffling and dynamic fed-batch strategies. J Ind Microbiol Biotechnol 41:1131–1143. https://doi.org/10.1007/s10295-014-1450-3
Dzhavakhiya VV, Voinova TM, Glagoleva EV, Petukhov DV, Ovchinnikov AI, Kartashov MI, Kuznetsov BB, Skryabin KG (2015) Strain improvement of Streptomyces xanthochromogenes RIA 1098 for enhanced pravastatin production at high compactin concentrations. Indian J Microbiol 55:440–446. https://doi.org/10.1007/s12088-015-0537-5
el-Naggar MY, Hassan MA, Said WYY, el-Aassar SA (2003) Effect of support materials on antibiotic MSW2000 production by immobilized Streptomyces violatus. J Gen Appl Microbiol 49:235–243. https://doi.org/10.2323/jgam.49.235
Endo K, Hosono K, Beppu T, Ueda K (2002) A novel extracytoplasmic phenol oxidase of Streptomyces: its possible involvement in the onset of morphogenesis. Microbiology (Reading) 148:1767–1776. https://doi.org/10.1099/00221287-148-6-1767
Ghosh S, Ahmad R, Gautam VK, Khare SK (2018) Cholesterol-oxidase-magnetic nanobioconjugates for the production of 4-cholesten-3-one and 4-cholesten-3, 7-dione. Bioresour Technol 254:91–96. https://doi.org/10.1016/j.biortech.2018.01.030
Guo J, Rao Z, Yang T, Man Z, Xu M, Zhang X (2014) High-level production of melanin by a novel isolate of Streptomyces kathirae. FEMS Microbiol Lett 357:85–91. https://doi.org/10.1111/1574-6968.12497
Guo J, Ma R, Su B, Li Y, Zhang J, Fang J (2016) Raising the avermectins production in Streptomyces avermitilis by utilizing nanosecond pulsed electric fields (nsPEFs). Sci Rep 6:1–10. https://doi.org/10.1038/srep25949
Hayashi K, Sugimoto H, Shinkyo R, Yamada M, Ikeda S, Ikushiro S, Kamakura M, Shiro Y, Sakaki T (2008) Structure-based design of a highly active vitamin D hydroxylase from Streptomyces griseolus CYP105A1. Biochemistry 47:11964–11972. https://doi.org/10.1021/bi801222d
Hormigo D, García-Hidalgo J, Acebal C, de la Mata I, Arroyo M (2012) Preparation and characterization of cross-linked enzyme aggregates (CLEAs) of recombinant poly-3-hydroxybutyrate depolymerase from Streptomyces exfoliatus. Bioresour Technol 115:177–182. https://doi.org/10.1016/j.biortech.2011.09.035
Hussain HA, Ward JM (2003) Enhanced heterologous expression of two Streptomyces griseolus cytochrome P450s and Streptomyces coelicolor ferredoxin reductase as potentially efficient hydroxylation catalysts. Appl Environ Microbiol 69:373–382. https://doi.org/10.1128/AEM.69.1.373-382.2003
Kim B-G, Jung B-R, Lee Y, Hur H-G, Lim Y, Ahn J-H (2006) Regiospecific flavonoid 7-O-methylation with Streptomyces avermitilis O-methyltransferase expressed in Escherichia coli. J Agric Food Chem 54:823–828. https://doi.org/10.1021/jf0522715
Kong D, Wang X, Nie J, Niu G (2019) Regulation of antibiotic production by signaling molecules in Streptomyces. Front Microbiol 10. https://doi.org/10.3389/fmicb.2019.02927
Kumar P, Sharma S, Malviya H, Balasubramanian R, Dalal A (2007) An improved fermentation process for preparing ascomycin Patent number WO 2007/029082A2
Li M, Zhang Z-J, Kong X-D, Yu H-L, Zhou J, Xu J-H (2017) Engineering Streptomyces coelicolor carbonyl reductase for efficient atorvastatin precursor synthesis. Appl Environ Microbiol 83. https://doi.org/10.1128/AEM.00603-17
Liu S-P, Yu P, Yuan P-H, Zhou Z-X, Bu Q-T, Mao X-M, Li Y-Q (2015) Sigma factor WhiGch positively regulates natamycin production in Streptomyces chattanoogensis L10. Appl Microbiol Biotechnol 99:2715–2726. https://doi.org/10.1007/s00253-014-6307-1
Liu Y, Huang L, Fu Y, Zheng D, Ma J, Li Y, Xu Z, Lu F (2019) A novel process for phosphatidylserine production using a Pichia pastoris whole-cell biocatalyst with overexpression of phospholipase D from Streptomyces halstedii in a purely aqueous system. Food Chem 274:535–542. https://doi.org/10.1016/j.foodchem.2018.08.105
López-García MT, Rioseras B, Yagüe P, Álvarez JR, Manteca Á (2014) Cell immobilization of Streptomyces coelicolor: effect on differentiation and actinorhodin production. Int Microbiol 17:75–80. https://doi.org/10.2436/20.1501.01.209
Martín JF, Liras P (2020) The balance metabolism safety net: integration of stress signals by interacting transcriptional factors in Streptomyces and related Actinobacteria. Front Microbiol 10. https://doi.org/10.3389/fmicb.2019.03120
Miranzo D, Seco EM, Cuesta T, Malpartida F (2010) Isolation and characterization of pcsB, the gene for a polyene carboxamide synthase that tailors pimaricin into AB-400. Appl Microbiol Biotechnol 85:1809–1819. https://doi.org/10.1007/s00253-009-2195-1
Molnár I, Jungmann V, Stege J, Trefzer A, Pachlatko JP (2006) Biocatalytic conversion of avermectin into 4″-oxo-avermectin: discovery, characterization, heterologous expression and specificity improvement of the cytochrome P450 enzyme. Biochem Soc Trans 34:1236–1240. https://doi.org/10.1042/BST0341236
Ng I-S, Ye C, Zhang Z, Lu Y, Jing K (2014) Daptomycin antibiotic production processes in fed-batch fermentation by Streptomyces roseosporus NRRL11379 with precursor effect and medium optimization. Bioprocess Biosyst Eng 37:415–423. https://doi.org/10.1007/s00449-013-1007-2
Olano C, Méndez C, Salas JA (2011) Molecular insights on the biosynthesis of antitumour compounds by actinomycetes. Microb Biotechnol 4:144–164. https://doi.org/10.1111/j.1751-7915.2010.00231.x
Olmos E, Mehmood N, Haj Husein L, Goergen J-L, Fick M, Delaunay S (2013) Effects of bioreactor hydrodynamics on the physiology of Streptomyces. Bioprocess Biosyst Eng 36:259–272. https://doi.org/10.1007/s00449-012-0794-1
Perdani MS, Sahlan M, Yohda M, Hermansyah H (2020) Immobilization of cholesterol oxidase from Streptomyces sp. on magnetite silicon dioxide by crosslinking method for cholesterol oxidation. Appl Biochem Biotechnol 191:968–980. https://doi.org/10.1007/s12010-020-03241-w
Pereira T, Nikodinovic J, Nakazono C, Dennis GR, Barrow KD, Chuck J-A (2008) Community structure and antibiotic production of Streptomyces nodosus bioreactors cultured in liquid environments. Microb Biotechnol 1:373–381. https://doi.org/10.1111/j.1751-7915.2008.00032.x
Perlman D (1952) Microbiological conversion of pregnenolone to progesterone. Science 115:529. https://doi.org/10.1126/science.115.2993.529
Pervaiz I, Ahmad S, Madni MA, Ahmad H, Khaliq FH (2013) Microbial biotransformation: a tool for drug designing (Review). Prikl Biokhim Mikrobiol 49:435–449. https://doi.org/10.7868/s0555109913050097
Qi H, Zhao S, Fu H, Wen J, Jia X (2014a) Enhancement of ascomycin production in Streptomyces hygroscopicus var. ascomyceticus by combining resin HP20 addition and metabolic profiling analysis. J Ind Microbiol Biotechnol 41:1365–1374. https://doi.org/10.1007/s10295-014-1473-9
Qi H, Zhao S, Wen J, Chen Y, Jia X (2014b) Analysis of ascomycin production enhanced by shikimic acid resistance and addition in Streptomyces hygroscopicus var. ascomyceticus. Biochem Eng J 82:124–133. https://doi.org/10.1016/j.bej.2013.11.006
Restaino OF, Marseglia M, De Castro C, Diana P, Forni P, Parrilli M, De Rosa M, Schiraldi C (2014) Biotechnological transformation of hydrocortisone to 16α-hydroxy hydrocortisone by Streptomyces roseochromogenes. Appl Microbiol Biotechnol 98:1291–1299. https://doi.org/10.1007/s00253-013-5384-x
Restaino OF, Marseglia M, Diana P, Borzacchiello MG, Finamore R, Vitiello M, D’Agostino A, De Rosa M, Schiraldi C (2016) Advances in the 16α-hydroxy transformation of hydrocortisone by Streptomyces roseochromogenes. Process Biochem 51:1–8. https://doi.org/10.1016/j.procbio.2015.11.009
Restaino OF, Barbuto Ferraiuolo S, Perna A, Cammarota M, Borzacchiello MG, Fiorentino A, Schiraldi C (2020) Biotechnological transformation of hydrocortisone into 16α-hydroxyprednisolone by coupling Arthrobacter simplex and Streptomyces roseochromogenes. Molecules 25:4912. https://doi.org/10.3390/molecules25214912
Roh C, Seo S-H, Choi K-Y, Cha M, Pandey BP, Kim J-H, Park J-S, Kim DH, Chang IS, Kim B-G (2009) Regioselective hydroxylation of isoflavones by Streptomyces avermitilis MA-4680. J Biosci Bioeng 108:41–46. https://doi.org/10.1016/j.jbiosc.2009.02.021
Romero-Rodríguez A, Rocha D, Ruiz-Villafan B, Tierrafría V, Rodríguez-Sanoja R, Segura-González D, Sánchez S (2016) Transcriptomic analysis of a classical model of carbon catabolite regulation in Streptomyces coelicolor. BMC Microbiol 16:77. https://doi.org/10.1186/s12866-016-0690-y
Ruiz B, Chávez A, Forero A, García-Huante Y, Romero A, Sánchez M, Rocha D, Sánchez B, Rodríguez-Sanoja R, Sánchez S, Langley E (2010) Production of microbial secondary metabolites: regulation by the carbon source. Crit Rev Microbiol 36:146–167. https://doi.org/10.3109/10408410903489576
Sánchez S, Chávez A, Forero A, García-Huante Y, Romero A, Sánchez M, Rocha D, Sánchez B, Ávalos M, Guzmán-Trampe S, Rodríguez-Sanoja R, Langley E, Ruiz B (2010) Carbon source regulation of antibiotic production. J Antibiot 63:442–459. https://doi.org/10.1038/ja.2010.78
Sanchez J, Yague P, Manteca A (2012) New insights in Streptomyces fermentations. Ferment Technol 1. https://doi.org/10.4172/2167-7972.1000e105
Scaffaro R, Lopresti F, Sutera A, Botta L, Fontana RM, Gallo G (2017) Plasma modified PLA electrospun membranes for actinorhodin production intensification in Streptomyces coelicolor immobilized-cell cultivations. Colloids Surf B: Biointerfaces 157:233–241. https://doi.org/10.1016/j.colsurfb.2017.05.060
Schmid A, Dordick JS, Hauer B, Kiener A, Wubbolts M, Witholt B (2001) Industrial biocatalysis today and tomorrow. Nature 409:258–268. https://doi.org/10.1038/35051736
Shen C, Zhao W, Liu X, Liu J (2019) Enzyme-catalyzed regio-selective demethylation of papaverine by CYP105D1. Biotechnol Lett 41:171–180. https://doi.org/10.1007/s10529-018-2626-0
Simpson FJ, McCoy E (1953) The amylases of five streptomycetes. Appl Microbiol 1:228–236
Singh R, Pandey B, Mathew CY (2014) Production, purification and optimization of streptomycin from isolated strain of Streptomyces griseus and analysis by HPLC. Indian J Sci Res 4(1):149–154
Song X, Zhang Y, Xue J, Li C, Wang Z, Wang Y (2018) Enhancing nemadectin production by Streptomyces cyaneogriseus ssp. noncyanogenus through quantitative evaluation and optimization of dissolved oxygen and shear force. Bioresour Technol 255:180–188. https://doi.org/10.1016/j.biortech.2017.09.033
Spasic J, Mandic M, Djokic L, Nikodinovic-Runic J (2018) Streptomyces spp. in the biocatalysis toolbox. Appl Microbiol Biotechnol 102:3513–3536. https://doi.org/10.1007/s00253-018-8884-x
Spycher PR, Amann CA, Wehrmüller JE, Hurwitz DR, Kreis O, Messmer D, Ritler A, Küchler A, Blanc A, Béhé M, Walde P, Schibli R (2017) Dual, site-specific modification of antibodies by using solid-phase immobilized microbial transglutaminase. Chembiochem 18:1923–1927. https://doi.org/10.1002/cbic.201700188
Tamburini E, Perito B, Mastromei G (2004) Growth phase-dependent expression of an endoglucanase encoding gene (eglS) in Streptomyces rochei A2. FEMS Microbiol Lett 237:267–272. https://doi.org/10.1111/j.1574-6968.2004.tb09706.x
Walker JB, Skorvaga M (1973) Phosphorylation of streptomycin and dihydrostreptomycin by Streptomyces. Enzymatic synthesis of different diphosphorylated derivatives. J Biol Chem 248:2435–2440
Wang X, Li D, Qu M, Durrani R, Yang B, Wang Y (2017) Immobilized MAS1 lipase showed high esterification activity in the production of triacylglycerols with n-3 polyunsaturated fatty acids. Food Chem 216:260–267. https://doi.org/10.1016/j.foodchem.2016.08.041
Wentzel A, Bruheim P, Øverby A, Jakobsen ØM, Sletta H, Omara WAM, Hodgson DA, Ellingsen TE (2012) Optimized submerged batch fermentation strategy for systems scale studies of metabolic switching in Streptomyces coelicolor A3(2). BMC Syst Biol 6:59. https://doi.org/10.1186/1752-0509-6-59
Wong JX, Ogura K, Chen S, Rehm BHA (2020) Bioengineered polyhydroxyalkanoates as immobilized enzyme scaffolds for industrial applications. Front Bioeng Biotechnol 8:156. https://doi.org/10.3389/fbioe.2020.00156
Yuan H, Wang H, Fidan O, Qin Y, Xiao G, Zhan J (2019) Identification of new glutamate decarboxylases from Streptomyces for efficient production of γ-aminobutyric acid in engineered Escherichia coli. J Biol Eng 13:24. https://doi.org/10.1186/s13036-019-0154-7
Yuan H, Zhang W, Xiao G, Zhan J (2020) Efficient production of gamma-aminobutyric acid by engineered Saccharomyces cerevisiae with glutamate decarboxylases from Streptomyces. Biotechnol Appl Biochem 67:240–248. https://doi.org/10.1002/bab.1840
Zhu H, Wang W, Liu J, Caiyin Q, Qiao J (2015) Immobilization of Streptomyces thermotolerans 11432 on polyurethane foam to improve production of acetylisovaleryltylosin. J Ind Microbiol Biotechnol 42:105–111. https://doi.org/10.1007/s10295-014-1545-x
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This work was financed by Campania Region-POR FESR 2007-2013 B25C13000290007 in the frame of project “Bio industrial processes-BIP.” S.B.F. is enrolled in a PhD program with an industrial project called “Streptomycetes as technological platform for the improvement of biotechnological productive processes of pharmaceutical active principles and/or nutraceuticals of industrial interests.”
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O.F.R. and S.B.F. conceived, drafted, and wrote the manuscript; C.S. obtained funds and reviewed the manuscript; M.C. performed SEM experiments. All authors read and approved the manuscript.
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Barbuto Ferraiuolo, S., Cammarota, M., Schiraldi, C. et al. Streptomycetes as platform for biotechnological production processes of drugs. Appl Microbiol Biotechnol 105, 551–568 (2021). https://doi.org/10.1007/s00253-020-11064-2
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DOI: https://doi.org/10.1007/s00253-020-11064-2