**Author details**

Angel Manteca\*, Beatriz Rioseras, Nathaly González-Quiñónez, Gemma Fernández-García and Paula Yagüe Área de Microbiología, Departamento de Biología Funcional e IUOPA, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain

\*Address all correspondence to: mantecaangel@uniovi.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**137**

*Mycelium Differentiation and Development of* Streptomyces *in Liquid Nonsporulating…*

pathway-specific regulatory gene redD in *S. coelicolor*. Journal of Zhejiang University. Science. 2005;**B**

[9] Yague P, Willemse J, Koning RI, Rioseras B, Lopez-Garcia MT, Gonzalez-Quinonez N, et al. Subcompartmentalization by crossmembranes during early growth of *Streptomyces hyphae*. Nature Communications. 2016;**7**:12467

[10] Manteca A, Alvarez R, Salazar N, Yague P, Sanchez J. Mycelium differentiation and antibiotic production in submerged cultures of *Streptomyces coelicolor*. Applied and Environmental Microbiology.

[11] Yague P, Rodriguez-Garcia A, Lopez-Garcia MT, Rioseras B, Martin JF, Sanchez J, et al. Transcriptomic analysis of liquid non-sporulating *Streptomyces coelicolor* cultures demonstrates the existence of a complex differentiation comparable to that occurring in solid sporulating cultures. PLoS One. 2014;**9**(1):e86296

[12] Manteca A, Sanchez J, Jung HR, Schwammle V, Jensen ON. Quantitative proteomics analysis of *Streptomyces coelicolor* development demonstrates that onset of secondary metabolism coincides with hypha differentiation. Molecular & Cellular Proteomics.

[13] Rioseras B, Shliaha PV, Gorshkov V, Yague P, Lopez-Garcia MT, Gonzalez-Quinonez N, et al. Quantitative proteome and phosphoproteome analyses of *Streptomyces coelicolor* reveal proteins and phosphoproteins modulating differentiation and secondary metabolism. Molecular & Cellular Proteomics. 2018;**17**(8):1591-1611

[14] Daniels R, Vanderleyden J, Michiels J. Quorum sensing and

2008;**74**(12):3877-3886

2010;**9**(7):1423-1436

(6, 6):464-469

*DOI: http://dx.doi.org/10.5772/intechopen.84182*

[1] Ruiz B, Chavez A, Forero A, Garcia-Huante Y, Romero A, Sanchez M, et al. Production of microbial secondary metabolites: Regulation by the carbon source. Critical Reviews in Microbiology. 2010;**36**(2):146-167

[2] Waksman SA. The Actinomycetes: Their Nature, Occurence, Activities and Importance. Waltham, Mass: Chronica

[3] Wildermuth H. Development and organization of the aerial mycelium in *Streptomyces coelicolor*. Journal of General Microbiology. 1970;**60**(1):43-50

[4] Chouayekh H, Nothaft H, Delaunay S, Linder M, Payrastre B, Seghezzi N, et al. Phosphoinositides are involved in control of the glucose-dependent growth resumption that follows the transition phase in *Streptomyces lividans*. Journal of Bacteriology.

[5] Granozzi C, Billetta R, Passantino R, Sollazzo M, Puglia AM. A breakdown in macromolecular synthesis preceding differentiation in *Streptomyces coelicolor* A3(2). Journal of General Microbiology.

[6] Novotna J, Vohradsky J, Berndt P, Gramajo H, Langen H, Li XM, et al. Proteomic studies of diauxic lag in the differentiating prokaryote *Streptomyces coelicolor* reveal a regulatory network of stress-induced proteins and central metabolic enzymes. Molecular Microbiology. 2003;**48**(5):1289-1303

[7] Vohradsky J, Li XM, Thompson CJ. Identification of procaryotic developmental stages by statistical analyses of two-dimensional gel patterns. Electrophoresis.

[8] Zhou LH, Li YQ, Li YQ, Wu D. Spatio-temporal expression of the

**References**

Botanica Co; 1950

2007;**189**(3):741-749

1990;**136**(4):713-716

1997;**18**(8):1418-1428

*Mycelium Differentiation and Development of* Streptomyces *in Liquid Nonsporulating… DOI: http://dx.doi.org/10.5772/intechopen.84182*

### **References**

*Growing and Handling of Bacterial Cultures*

**136**

**Author details**

provided the original work is properly cited.

Gemma Fernández-García and Paula Yagüe

Medicina, Universidad de Oviedo, Oviedo, Spain

\*Address all correspondence to: mantecaangel@uniovi.es

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Área de Microbiología, Departamento de Biología Funcional e IUOPA, Facultad de

Angel Manteca\*, Beatriz Rioseras, Nathaly González-Quiñónez,

[1] Ruiz B, Chavez A, Forero A, Garcia-Huante Y, Romero A, Sanchez M, et al. Production of microbial secondary metabolites: Regulation by the carbon source. Critical Reviews in Microbiology. 2010;**36**(2):146-167

[2] Waksman SA. The Actinomycetes: Their Nature, Occurence, Activities and Importance. Waltham, Mass: Chronica Botanica Co; 1950

[3] Wildermuth H. Development and organization of the aerial mycelium in *Streptomyces coelicolor*. Journal of General Microbiology. 1970;**60**(1):43-50

[4] Chouayekh H, Nothaft H, Delaunay S, Linder M, Payrastre B, Seghezzi N, et al. Phosphoinositides are involved in control of the glucose-dependent growth resumption that follows the transition phase in *Streptomyces lividans*. Journal of Bacteriology. 2007;**189**(3):741-749

[5] Granozzi C, Billetta R, Passantino R, Sollazzo M, Puglia AM. A breakdown in macromolecular synthesis preceding differentiation in *Streptomyces coelicolor* A3(2). Journal of General Microbiology. 1990;**136**(4):713-716

[6] Novotna J, Vohradsky J, Berndt P, Gramajo H, Langen H, Li XM, et al. Proteomic studies of diauxic lag in the differentiating prokaryote *Streptomyces coelicolor* reveal a regulatory network of stress-induced proteins and central metabolic enzymes. Molecular Microbiology. 2003;**48**(5):1289-1303

[7] Vohradsky J, Li XM, Thompson CJ. Identification of procaryotic developmental stages by statistical analyses of two-dimensional gel patterns. Electrophoresis. 1997;**18**(8):1418-1428

[8] Zhou LH, Li YQ, Li YQ, Wu D. Spatio-temporal expression of the pathway-specific regulatory gene redD in *S. coelicolor*. Journal of Zhejiang University. Science. 2005;**B** (6, 6):464-469

[9] Yague P, Willemse J, Koning RI, Rioseras B, Lopez-Garcia MT, Gonzalez-Quinonez N, et al. Subcompartmentalization by crossmembranes during early growth of *Streptomyces hyphae*. Nature Communications. 2016;**7**:12467

[10] Manteca A, Alvarez R, Salazar N, Yague P, Sanchez J. Mycelium differentiation and antibiotic production in submerged cultures of *Streptomyces coelicolor*. Applied and Environmental Microbiology. 2008;**74**(12):3877-3886

[11] Yague P, Rodriguez-Garcia A, Lopez-Garcia MT, Rioseras B, Martin JF, Sanchez J, et al. Transcriptomic analysis of liquid non-sporulating *Streptomyces coelicolor* cultures demonstrates the existence of a complex differentiation comparable to that occurring in solid sporulating cultures. PLoS One. 2014;**9**(1):e86296

[12] Manteca A, Sanchez J, Jung HR, Schwammle V, Jensen ON. Quantitative proteomics analysis of *Streptomyces coelicolor* development demonstrates that onset of secondary metabolism coincides with hypha differentiation. Molecular & Cellular Proteomics. 2010;**9**(7):1423-1436

[13] Rioseras B, Shliaha PV, Gorshkov V, Yague P, Lopez-Garcia MT, Gonzalez-Quinonez N, et al. Quantitative proteome and phosphoproteome analyses of *Streptomyces coelicolor* reveal proteins and phosphoproteins modulating differentiation and secondary metabolism. Molecular & Cellular Proteomics. 2018;**17**(8):1591-1611

[14] Daniels R, Vanderleyden J, Michiels J. Quorum sensing and swarming migration in bacteria. FEMS Microbiology Reviews. 2004;**28**(3):261-289

[15] Manteca A, Sanchez J. Streptomyces development in colonies and soils. Applied and Environmental Microbiology. 2009;**75**(9):2920-2924

[16] Pamboukian CR, Facciotti MC. Production of antitumoral retamycin during fed-batch fermentations of *Streptomyces olindensis*. Applied Biochemistry and Biotechnology. 2004;**112**(2):111-122

[17] Yang YK, Morikawa M, Shimizu H, Shioya S, Suga KI, Nihira T, et al. Image analysis of mycelial morphology in virginiamycin production by batch culture of *Streptomyces virginiae*. Journal of Fermentation and Bioengineering. 1996;**81**:7-12

[18] Dunstan GH, Avignone-Rossa C, Langley D, Bushell ME. The vancomycin biosynthetic pathway is induced in oxygen-limited *Amycolatopsis orientalis* (ATCC 19795) cultures that do not produce antibiotic. Enzyme and Microbial Technology. 2000;**27**:502-510

[19] Clark GJ, Langley D, Bushell ME. Oxygen limitation can induce microbial secondary metabolite formation, investigations with miniature electrodes in shaker and bioreactor culture. Microbiology. 1995;**141**:663-669

[20] Rioseras B, Lopez-Garcia MT, Yague P, Sanchez J, Manteca A. Mycelium differentiation and development of *Streptomyces coelicolor* in lab-scale bioreactors: Programmed cell death, differentiation, and lysis are closely linked to undecylprodigiosin and actinorhodin production. Bioresource Technology. 2014;**151**:191-198

[21] Petrus ML, Vijgenboom E, Chaplin AK, Worrall JA, van Wezel GP, Claessen D. The DyP-type peroxidase

DtpA is a Tat-substrate required for GlxA maturation and morphogenesis in Streptomyces. Open Biology. 2016;**6**(1):150149

[22] Zacchetti B, Willemse J, Recter B, van Dissel D, van Wezel GP, Wosten HA, et al. Aggregation of germlings is a major contributing factor towards mycelial heterogeneity of Streptomyces. Scientific Reports. 2016;**6**:27045

[23] Wentzel A, Bruheim P, Overby A, Jakobsen OM, Sletta H, Omara WA, et al. Optimized submerged batch fermentation strategy for systems scale studies of metabolic switching in *Streptomyces coelicolor* A3(2). BMC Systems Biology. 2012;**6**:59

[24] Yague P, Lopez-Garcia MT, Rioseras B, Sanchez J, Manteca A. Presporulation stages of Streptomyces differentiation: State-of-the-art and future perspectives. FEMS Microbiology Letters. 2013;**342**(2):79-88

[25] Roubos JA, Krabben P, Luiten RG, Verbruggen HB, Heijnen JJ. A quantitative approach to characterizing cell lysis caused by mechanical agitation of *Streptomyces clavuligerus*. Biotechnology Progress. 2001;**17**(2):336-347

[26] Techapun C, Poosaran N, Watanabe M, Sasaki K. Optimization of aeration and agitation rates to improve cellulase-free xylanase production by thermotolerant *Streptomyces* sp. Ab106 and repeated fed-batch cultivation using agricultural waste. Journal of Bioscience and Bioengineering. 2003;**95**(3):298-301

[27] Shih IL, Shen MH. Optimization of cell growth and poly(ɛ-lysine) production in batch and fed-batch cultures by *Streptomyces albulus* IFO 14147. Process Biochemistry. 2006;**41**:1644-1649

[28] Ozergin-Ulgen K, Mavituna F. Actinorhodin production by

**139**

*Mycelium Differentiation and Development of* Streptomyces *in Liquid Nonsporulating…*

[36] Horinouchi S, Beppu T. Autoregulatory factors and communication in actinomycetes. Annual Review of Microbiology.

[37] Berdy J. Bioactive microbial metabolites. Journal of Antibiotics

[38] Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009;**325**(5944):1089-1093

[40] Weissman KJ, Leadlay PF. Combinatorial biosynthesis of reduced polyketides. Nature Reviews. Microbiology. 2005;**3**(12):925-936

(Tokyo). 2017;**70**(8):865-870

[42] Manivasagan P, Kang KH, Sivakumar K, Li-Chan EC, Oh HM, Kim SK. Marine actinobacteria: An important source of bioactive natural products. Environmental Toxicology and Pharmacology. 2014;**38**(1):172-188

[43] Parrot D, Legrave N, Delmail D, Grube M, Suzuki M, Tomasi S.

Medica. 2016;**82**(13):1143-1152

[44] Genilloud O. The re-emerging role of microbial natural products in antibiotic discovery. Antonie Van Leeuwenhoek. 2014;**106**(1):173-188

[45] Marmann A, Aly AH, Lin W, Wang B, Proksch P. Co-cultivation—A

powerful emerging tool for

Review—Lichen-associated bacteria as a hot spot of chemodiversity: Focus on uncialamycin, a promising compound for future medicinal applications. Planta

[41] Onaka H. Novel antibiotic screening methods to awaken silent or cryptic secondary metabolic pathways in actinomycetes. Journal of Antibiotics

[39] Hopwood DA. Streptomyces in Nature and Medicine: The Antibiotic Makers. New York, Oxford: Oxford

(Tokyo). 2005;**58**(1):1-26

University Press; 2007

1992;**46**:377-398

*DOI: http://dx.doi.org/10.5772/intechopen.84182*

*Streptomyces coelicolor* A3(2): Kinetic parameters related to growth, substrate uptake and production. Applied Microbiology and Biotechnology.

[29] van Wezel GP, Krabben P, Traag BA, Keijser BJ, Kerste R, Vijgenboom E, et al. Unlocking *Streptomyces* spp. for use as sustainable industrial production platforms by morphological engineering.

Microbiology. 2006;**72**(8):5283-5288

[30] Magnolo SK, Leenutaphong DL, DeModena JA, Curtis JE, Bailey JE, Galazzo JL, et al. Actinorhodin production by *Streptomyces coelicolor* and growth of *Streptomyces lividans* are improved by the expression of a bacterial hemoglobin. Biotechnology

Applied and Environmental

(N. Y). 1991;**9**(5):473-476

[31] Yegneswaran PK, Gray MR,

*clavuligerus*. Biotechnology and

1952;**63**(2):253-262

1989;**135**:2483-2491

2001;**4**(6):667-673

2010;**34**(2):171-198

[34] Chater KF. Regulation of sporulation in *Streptomyces coelicolor* A3(2): A checkpoint multiplex? Current Opinion in Microbiology.

[35] Chater KF, Biro S, Lee KJ, Palmer T, Schrempf H. The complex extracellular biology of Streptomyces.

FEMS Microbiology Reviews.

Thompson BG. Experimental simulation of dissolved oxygen fluctuations in large fermentors: Effect on *Streptomyces* 

Bioengineering. 1991;**38**(10):1203-1209

[32] Perlman D, Wagman GH. Studies on the utilization of lipids by *Streptomyces griseus*. Journal of Bacteriology.

[33] Daza A, Martin JF, Dominguez A, Gil JA. Sporulation of several species of Streptomyces in submerged cultures after nutritional downshift. Journal of General Microbiology.

1993;**40**:457-462

*Mycelium Differentiation and Development of* Streptomyces *in Liquid Nonsporulating… DOI: http://dx.doi.org/10.5772/intechopen.84182*

*Streptomyces coelicolor* A3(2): Kinetic parameters related to growth, substrate uptake and production. Applied Microbiology and Biotechnology. 1993;**40**:457-462

*Growing and Handling of Bacterial Cultures*

[15] Manteca A, Sanchez J. Streptomyces

DtpA is a Tat-substrate required for GlxA maturation and morphogenesis in Streptomyces. Open Biology.

[22] Zacchetti B, Willemse J, Recter B, van Dissel D, van Wezel GP, Wosten HA, et al. Aggregation of germlings is a major contributing factor towards mycelial heterogeneity of Streptomyces.

[23] Wentzel A, Bruheim P, Overby A, Jakobsen OM, Sletta H, Omara WA, et al. Optimized submerged batch fermentation strategy for systems scale studies of metabolic switching in *Streptomyces coelicolor* A3(2). BMC

Scientific Reports. 2016;**6**:27045

Systems Biology. 2012;**6**:59

Letters. 2013;**342**(2):79-88

2001;**17**(2):336-347

2006;**41**:1644-1649

[25] Roubos JA, Krabben P, Luiten RG, Verbruggen HB, Heijnen JJ. A quantitative approach to characterizing cell lysis caused by mechanical agitation of *Streptomyces clavuligerus*. Biotechnology Progress.

[26] Techapun C, Poosaran N, Watanabe M, Sasaki K. Optimization of aeration

cellulase-free xylanase production by thermotolerant *Streptomyces* sp. Ab106 and repeated fed-batch cultivation using agricultural waste. Journal of Bioscience and Bioengineering. 2003;**95**(3):298-301

[27] Shih IL, Shen MH. Optimization of cell growth and poly(ɛ-lysine) production in batch and fed-batch cultures by *Streptomyces albulus* IFO 14147. Process Biochemistry.

[28] Ozergin-Ulgen K, Mavituna F. Actinorhodin production by

and agitation rates to improve

[24] Yague P, Lopez-Garcia MT, Rioseras B, Sanchez J, Manteca A. Presporulation stages of Streptomyces differentiation: State-of-the-art and future perspectives. FEMS Microbiology

2016;**6**(1):150149

swarming migration in bacteria. FEMS Microbiology Reviews.

development in colonies and soils. Applied and Environmental Microbiology. 2009;**75**(9):2920-2924

[16] Pamboukian CR, Facciotti MC. Production of antitumoral retamycin during fed-batch fermentations of *Streptomyces olindensis*. Applied Biochemistry and Biotechnology. 2004;**112**(2):111-122

[17] Yang YK, Morikawa M, Shimizu H, Shioya S, Suga KI, Nihira T, et al. Image analysis of mycelial morphology in virginiamycin production by batch culture of *Streptomyces virginiae*. Journal of Fermentation and Bioengineering.

[18] Dunstan GH, Avignone-Rossa C, Langley D, Bushell ME. The vancomycin biosynthetic pathway is induced in oxygen-limited *Amycolatopsis orientalis* (ATCC 19795) cultures that do not produce antibiotic. Enzyme and Microbial Technology. 2000;**27**:502-510

[19] Clark GJ, Langley D, Bushell ME. Oxygen limitation can induce microbial secondary metabolite formation, investigations with miniature electrodes in shaker and bioreactor culture. Microbiology.

[20] Rioseras B, Lopez-Garcia MT, Yague P, Sanchez J, Manteca A. Mycelium differentiation and development of *Streptomyces coelicolor* in lab-scale bioreactors: Programmed cell death, differentiation, and lysis are closely linked to undecylprodigiosin and actinorhodin production. Bioresource

Technology. 2014;**151**:191-198

AK, Worrall JA, van Wezel GP, Claessen D. The DyP-type peroxidase

[21] Petrus ML, Vijgenboom E, Chaplin

1995;**141**:663-669

2004;**28**(3):261-289

1996;**81**:7-12

**138**

[29] van Wezel GP, Krabben P, Traag BA, Keijser BJ, Kerste R, Vijgenboom E, et al. Unlocking *Streptomyces* spp. for use as sustainable industrial production platforms by morphological engineering. Applied and Environmental Microbiology. 2006;**72**(8):5283-5288

[30] Magnolo SK, Leenutaphong DL, DeModena JA, Curtis JE, Bailey JE, Galazzo JL, et al. Actinorhodin production by *Streptomyces coelicolor* and growth of *Streptomyces lividans* are improved by the expression of a bacterial hemoglobin. Biotechnology (N. Y). 1991;**9**(5):473-476

[31] Yegneswaran PK, Gray MR, Thompson BG. Experimental simulation of dissolved oxygen fluctuations in large fermentors: Effect on *Streptomyces clavuligerus*. Biotechnology and Bioengineering. 1991;**38**(10):1203-1209

[32] Perlman D, Wagman GH. Studies on the utilization of lipids by *Streptomyces griseus*. Journal of Bacteriology. 1952;**63**(2):253-262

[33] Daza A, Martin JF, Dominguez A, Gil JA. Sporulation of several species of Streptomyces in submerged cultures after nutritional downshift. Journal of General Microbiology. 1989;**135**:2483-2491

[34] Chater KF. Regulation of sporulation in *Streptomyces coelicolor* A3(2): A checkpoint multiplex? Current Opinion in Microbiology. 2001;**4**(6):667-673

[35] Chater KF, Biro S, Lee KJ, Palmer T, Schrempf H. The complex extracellular biology of Streptomyces. FEMS Microbiology Reviews. 2010;**34**(2):171-198

[36] Horinouchi S, Beppu T. Autoregulatory factors and communication in actinomycetes. Annual Review of Microbiology. 1992;**46**:377-398

[37] Berdy J. Bioactive microbial metabolites. Journal of Antibiotics (Tokyo). 2005;**58**(1):1-26

[38] Fischbach MA, Walsh CT. Antibiotics for emerging pathogens. Science. 2009;**325**(5944):1089-1093

[39] Hopwood DA. Streptomyces in Nature and Medicine: The Antibiotic Makers. New York, Oxford: Oxford University Press; 2007

[40] Weissman KJ, Leadlay PF. Combinatorial biosynthesis of reduced polyketides. Nature Reviews. Microbiology. 2005;**3**(12):925-936

[41] Onaka H. Novel antibiotic screening methods to awaken silent or cryptic secondary metabolic pathways in actinomycetes. Journal of Antibiotics (Tokyo). 2017;**70**(8):865-870

[42] Manivasagan P, Kang KH, Sivakumar K, Li-Chan EC, Oh HM, Kim SK. Marine actinobacteria: An important source of bioactive natural products. Environmental Toxicology and Pharmacology. 2014;**38**(1):172-188

[43] Parrot D, Legrave N, Delmail D, Grube M, Suzuki M, Tomasi S. Review—Lichen-associated bacteria as a hot spot of chemodiversity: Focus on uncialamycin, a promising compound for future medicinal applications. Planta Medica. 2016;**82**(13):1143-1152

[44] Genilloud O. The re-emerging role of microbial natural products in antibiotic discovery. Antonie Van Leeuwenhoek. 2014;**106**(1):173-188

[45] Marmann A, Aly AH, Lin W, Wang B, Proksch P. Co-cultivation—A powerful emerging tool for

enhancing the chemical diversity of microorganisms. Marine Drugs. 2014;**12**(2):1043-1065

[46] Liu G, Chater KF, Chandra G, Niu G, Tan H. Molecular regulation of antibiotic biosynthesis in streptomyces. Microbiology and Molecular Biology Reviews. 2013;**77**(1):112-143

[47] Gomez-Escribano JP, Bibb MJ. Engineering *Streptomyces coelicolor* for heterologous expression of secondary metabolite gene clusters. Microbial Biotechnology. 2011;**4**(2):207-215

[48] Manteca A, Yague P. Streptomyces differentiation in liquid cultures as a trigger of secondary metabolism. Antibiotics (Basel). 2018;**7**(2)

[49] Marin L, Gutierrez-Del-Rio I, Yague P, Manteca A, Villar CJ, Lombo F. De novo biosynthesis of apigenin, luteolin, and eriodictyol in the actinomycete *Streptomyces albus* and production improvement by feeding and spore conditioning. Frontiers in Microbiology. 2017;**8**:921

[50] Treppiccione L, Ottombrino A, Luongo D, Maurano F, Manteca A, Lombó F, et al. Development of gluten with immunomodulatory properties using mTG-active food grade supernatants from *Streptomyces mobaraensis* cultures. Journal of Functional Foods. 2017;**34**:390-397

[51] Kendrick KE, Ensign JC. Sporulation of *Streptomyces griseus* in submerged culture. Journal of Bacteriology. 1983;**155**(1):357-366

[52] Glazebrook MA, Doull JL, Stuttard C, Vining LC. Sporulation of *Streptomyces venezuelae* in submerged cultures. Journal of General Microbiology. 1990;**136**(3):581-588

*Growing and Handling of Bacterial Cultures*

enhancing the chemical diversity of microorganisms. Marine Drugs.

[46] Liu G, Chater KF, Chandra G, Niu G, Tan H. Molecular regulation of antibiotic biosynthesis in streptomyces. Microbiology and Molecular Biology

Reviews. 2013;**77**(1):112-143

[47] Gomez-Escribano JP, Bibb MJ. Engineering *Streptomyces* 

of secondary metabolite gene clusters. Microbial Biotechnology.

2011;**4**(2):207-215

2017;**8**:921

*coelicolor* for heterologous expression

[48] Manteca A, Yague P. Streptomyces differentiation in liquid cultures as a trigger of secondary metabolism. Antibiotics (Basel). 2018;**7**(2)

[49] Marin L, Gutierrez-Del-Rio I, Yague P, Manteca A, Villar CJ, Lombo F. De novo biosynthesis of apigenin, luteolin, and eriodictyol in the actinomycete *Streptomyces albus* and production improvement by feeding and spore conditioning. Frontiers in Microbiology.

[50] Treppiccione L, Ottombrino A, Luongo D, Maurano F, Manteca A, Lombó F, et al. Development of gluten with immunomodulatory properties using mTG-active food grade supernatants from *Streptomyces mobaraensis* cultures. Journal of Functional Foods. 2017;**34**:390-397

[51] Kendrick KE, Ensign JC. Sporulation of *Streptomyces griseus* in submerged culture. Journal of Bacteriology.

1983;**155**(1):357-366

[52] Glazebrook MA, Doull JL, Stuttard C, Vining LC. Sporulation of *Streptomyces venezuelae* in submerged

cultures. Journal of General Microbiology. 1990;**136**(3):581-588

2014;**12**(2):1043-1065

**140**
