Skip to main content

Advertisement

SpringerLink
Log in

Optimization of submerged fermentation conditions for immunosuppressant mycophenolic acid production by Penicillium roqueforti isolated from blue-molded cheeses: enhanced production by ultraviolet and gamma irradiation

  • Original Paper
  • Published:
World Journal of Microbiology and Biotechnology Aims and scope Submit manuscript

Abstract

Mycophenolic acid (MPA) is a promising drug owing to its immunosuppressive and biological activities. In this study, two strains of Penicillium roqueforti designated as AG101 and LG109 were selected among several strains isolated from Roquefort cheese samples on the basis of their activity for MPA-producing ability. The appropriate fermentation conditions necessary for MPA biosynthesis by the two respective fungal strains were investigated. These conditions included selection of the cultivation medium, agitation rate, incubation temperature, fermentation time, pH value, inoculum size, and fermentation medium volume. Maximum MPA productivities were maintained when the fermentation process was carried out using a medium composed of (g l−1): Sucrose, 30; peptone, 5.0; KH2PO4, 1.0; MgSO4·7H2O, 0.5 and KCl, 0.5; pH 6.0, inoculated with an inoculum size of 6.0 % (v/v), and incubated at 25 °C for 10 days at 120 rpm. The potentiality of both P. roqueforti strains for further improvement of MPA production was applied by mutagenesis through exposure to irradiation by ultraviolet rays (UV, 254 nm) for different periods of time and gamma rays at various doses (KGy). The dry cell weight of both irradiated fungal strains showed a greater reduction when irradiated either with UV or gamma rays. However, the MPA yield of both strains was increased by 1.27–1.39 fold when irradiated with UV rays and by 2.11–2.33 fold when irradiated with gamma rays, as compared with the respective controls (non-irradiated cultures). These findings indicate the future possibility to reduce the cost of producing fermentation-based drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Allison AC, Eugui EM (1996) Purine metabolism and immunosuppressive effects of mycophenolate mofetil. Clin Transplant 10:77–84

    CAS  Google Scholar 

  • Applegate KL, Chipley JR (1974) Effects of 60Co gamma irradiation on aflatoxin B1 and B2 production by Aspergillus flavus. Mycologia 66:436–445

    Article  CAS  Google Scholar 

  • Ardestani F, Fatemi SSA, Yakhchali B, Hosseyni SM, Najafpour G (2010) Evaluation of mycophenolic acid production by Penicillium brevicompactum MUCL 19011 in batch and continuous submerged cultures. Biochem Eng J 50:99–103

    Article  CAS  Google Scholar 

  • Ardestani F, Fatemi SSA, Yakhchali B (2011) Enhanced mycophenolic acid production by Penicillium brevicompactum with enzymatically hydrolyzed casein. World Acad Sci Eng Technol 5:209–212, International Science Index vol:5, no:1, 2011 waset.org/Publication/15660. Accessed 27 Jan 2011

  • Balakrishnan K, Pandey A (1996) Influence of amino acids on the biosynthesis of cyclosporin A by Tolypocladium inflatum. Appl Microbiol Biotechnol 45:800–803

    Article  CAS  Google Scholar 

  • Balaraman K, Mathew N (2006) Optimization of media composition for the production of cyclosporin A by Tolypocladium species. Indian J Med Res 123:525–530

    CAS  Google Scholar 

  • Bentley R (2000) Mycophenolic acid: a one hundred year odyssey from antibiotic to immunosuppressant. Chem Rev 100:3801–3826

    Article  CAS  Google Scholar 

  • Braga GU, Rangel DE, Flint SD, Miller CD, Anderson AJ, Roberts DW (2002) Damage and recovery from UV-B exposure in conidia of the entomopathogens Verticillium lecanii and Aphanocladium album. Mycologia 94:912–920

    Article  Google Scholar 

  • Cadet J, Delatour T, Douki T, Gasparutto D, Pouget JP, Ravanat JL, Sauvaigo S (1999) Hydroxyl radicals and DNA base damage. Mutat Res 424:9–21

    Article  CAS  Google Scholar 

  • Chopra VL (2005) Mutagenesis: investigating the process and processing the outcome for crop improvement. Curr Sci 89:353–359

    CAS  Google Scholar 

  • Diamond MS, Zachariah M, Harris E (2002) Mycophenolic acid inhibits Dengue virus infection by preventing replication of viral RNA. Virology 304:211–221

    Article  CAS  Google Scholar 

  • Doerfler DL, Bartman CD, Campbell IM (1979) Mycophenolic acid production by Penicillium brevicompactum in two media. Can J Microbiol 25:940–943

    Article  CAS  Google Scholar 

  • Engel G, von Milczewski KE, Prokopek D, Teuber M (1982) Strain-specific synthesis of mycophenolic acid by Penicillium roqueforti in blue-veined cheese. Appl Environ Microbiol 43:1034–1040

    CAS  Google Scholar 

  • Epinette WW, Parker CM, Jones EL, Greist MC (1987) Mycophenolic acid for psoriasis. A review of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol 17:962–971

    Article  CAS  Google Scholar 

  • Frisvad JC, Samson RA (2004) Polyphasic taxonomy of Penicillium subgenus Penicillium. A guide to identification food and air-borne terverticillate penicillia and their mycotoxins. In: Samson RA, Frisvad JC (eds) Penicillium subgenus Penicillium: new taxonomic schemes, mycotoxins and other extrolites. Stud Mycol 49:1–174

  • Gao XR, Yao SJ, Zhu J, Qing YL, Zhang XL (2007) Optimization of submerged fermentation conditions of Penicillium brevicompactum producing mycophenolic acid. Chin J Pharm 38:273–276

    CAS  Google Scholar 

  • Ignoffo CM, Garcia C (1992) Influence of conidial colour on inactivation of several entomogenous fungi by stimulated sunlight. Environ Entomol 21:913–917

    Google Scholar 

  • Ismaiel AA, El-Sayed EA, Mahmoud AA (2010) Some optimal culture conditions for production of cyclosporin A by Fusarium roseum. Braz J Microbiol 41:1112–1123

  • Jonsson CA, Carlesten H (2003) Mycophenolic acid inhibits inosine 5′-monophosphate dehydrogenase and suppresses immunoglobulin and cytokine production of B cells. Int Immunopharmacol 3:31–37

    Article  CAS  Google Scholar 

  • Lafont P, Debeaupuis J-P, Gaillardin M, Payen J (1979a) Production of mycophenolic acid by Penicillium roqueforti strains. Appl Environ Microbiol 37:365–368

    CAS  Google Scholar 

  • Lafont P, Siriwardana MG, Combemale I, Lafont J (1979b) Mycophenolic acid in marketed cheeses. Food Cosmet Toxicol 17:147–149

    Article  CAS  Google Scholar 

  • Lou X, Jia X, Lou S, Zhang H (2007) Screening mycophenoilc acid high producing strain with UV and heavy metal ion resistance mutation. Chin J Antibiot 32:536–537

    CAS  Google Scholar 

  • Mele TS, Halloran PF (2000) The use of mycophenolate mofetil in transplant recipients. J Immunopharmacol 47:215–245

    Article  CAS  Google Scholar 

  • Moubasher AH (1993) Soil fungi in Qatar and other Arab Countries. The Centre for Scientific and Applied Research, Doha

    Google Scholar 

  • Nicoletti R, De Stefano M, De Stefano S, Trincone A, Marziano F (2004) Antagonism against Rhizoctonia solani and fungitoxic metabolite production by some Penicillium isolates. Mycopathologia 158:465–474

    Article  CAS  Google Scholar 

  • Ozaki H, Kubota K, Takahashi H (1987) Effects of various adsorbents on mycelium formation and mycophenolic acid production by Penicillium brevicompactum. Biosci Biotechnol Biochem 51:2503–2508

    CAS  Google Scholar 

  • Parekh S, Vinci VA, Strobel RJ (2000) Improvement of microbial strains and fermentation processes. Appl Microbiol Biotechnol 54:287–301

    Article  CAS  Google Scholar 

  • Paster N, Barkai-Golan R, Padova R (1985) Effect of gamma radiation on ochratoxin production by the fungus Aspergillus ochraceus. J Sci Food Agric 36:445–449

    Article  CAS  Google Scholar 

  • Pokluda Z, Satke J, Vala V, Valik J (2008) Regulation of acid metabolite production. US Patent 0009050 A1

  • Puel O, Tadrist S, Galtier P, Oswald IP, Delaforge M (2005) Byssochlamys nivea as a source of mycophenolic acid. Appl Environ Microbiol 71:550–553

    Article  CAS  Google Scholar 

  • Queener SW, Nash III CH (1978) Procedure for obtaining Penicillium species mutants with improved ability to synthesize mycophenolic acid. US Patent 4, 115,197

  • Ramos-Ponce LM, Contreras-Esquivel JC, Saenz JM, Lara-Cisneros G, Garza-Garcia Y (2012) Study on production of mycophenolic acid by Penicillium pinophilum using response surface methodology. 2nd Portuguese Meeting, Institute of Electrical and Electronics Engineers, Bioengineering (ENBENG) pp 1–4

  • Rho Y-T (2011) Effects of carbon and nitrogen sources on immunosuppressant mycophenolic acid fermentation by Penicillium brevicompactum. Korean J Microbiol 47:249–254

    Google Scholar 

  • Ribeiro J, Cavaglieri L, Vital H, Cristofolini A, Merkis C, Astoreca A, Orlando J, Carú M, Dalcero A, Rosa CA (2011) Effect of gamma radiation on Aspergillus flavus and Aspergillus ochraceus ultrastructure and mycotoxin production. Radiat Phys Chem 80:658–663

    Article  CAS  Google Scholar 

  • Sadhukhan AK, Murthy MVR, Kumar RA, Mohan EVS, Vandana G, Bhar C, Rao KV (1999) Optimization of mycophenolic acid production in solid state fermentation using response surface methodology. J Ind Microbiol Biotechnol 22:33–38

    Article  CAS  Google Scholar 

  • Shu CH, Peng JC, Tsai CC (2010) Effects of light intensity and light wavelength on the production of mycophenolic acid by Penicillium brevicompactum in batch cultures. Enzyme Microb Technol 46:466–471

    Article  CAS  Google Scholar 

  • Thacker J (1999) Repair of ionizing radiation damage in mammalian cells. Alternative pathways and their fidelity. CR Acad Sci III 322:103–108

    Article  CAS  Google Scholar 

  • Torrenegra RD, Baquero JE, Calderon JS (2005) Antibacterial activity and complete 1H and 13C NMR assignment of mycophenolic acid isolated from Penicillium verrucosum. Rev Lat Am Quim 33:76–81

    CAS  Google Scholar 

  • Tressler RJ, Garvin LJ, Slate DL (1994) Anti-tumor activity of mycophenolate mofetil against human and mouse tumors in vivo. Int J Cancer 57:568–573

    Article  CAS  Google Scholar 

  • Ulevičius V, Pečiulyte D, Plauškaite K, Špirkauskaite N (2008) Resistance of airborne fungal propagules to ultraviolet irradiation: laboratory study. Lith J Phys 48:265–273

    Article  Google Scholar 

  • Vinokurova NG, Ivanushkina NE, Kochkina GA, Arinbasarov MU, Ozerskaya SM (2005) Production of mycophenolic acid by fungi of genus Penicillium link. Appl Biochem Microbiol 41:95–98

    Article  CAS  Google Scholar 

  • Willocquet L, Colombet D, Rougier M, Fargues J, Clerjeau M (1996) Effects of radiation, especially ultraviolet B, on conidial germination and mycelial growth of grape powdery mildew. Eur J Plant Pathol 102:441–449

    Article  Google Scholar 

  • Wirsching S, Morgan GP, Sullivan DJ, Coleman DC, Morschhäuser J (2001) MDR1-mediated drug resistance in Candida dubliniensis. Antimicrob Agents Chemother 45:3416–3421

    Article  CAS  Google Scholar 

  • Xiang-tian Q, Yong-feng X, Zhao-bing C (2005) Studies on mutagensis and fermentation of mycophenolic acid producing strain. Chin J Antibiot 30:426–427

    Google Scholar 

  • Zhao Y, Ang WT, Xing J, Zhang J, Chen J (2012) Applications of ultrasound to enhance mycophenolic acid production. Ultrasound Med Biol 38:1582–1588

    Article  Google Scholar 

Download references

Acknowledgments

We thank the staff members of Central Laboratories of Isotopes Applications Division, Nuclear Research Center, Atomic Energy Authority, Inshas for excellent technical assistance in performing HPLC analysis. This work was supported in part by the Nuclear Research Center, Atomic Energy Authority, Inshas, Egypt.

Conflict of interest

The authors declare that they have no conflicts of interest concerning this article.

Author information

Authors and Affiliations

  1. Department of Botany and Microbiology, Faculty of Science, Zagazig University, Zagazig, 44519, Egypt

    Ahmed A. Ismaiel & El-Sayed R. El-Sayed

  2. Plant Research Department, Nuclear Research Center, Atomic Energy Authority, Inshas, Egypt

    Ashraf S. Ahmed & El-Sayed R. El-Sayed

Authors
  1. Ahmed A. Ismaiel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ashraf S. Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. El-Sayed R. El-Sayed
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ahmed A. Ismaiel.

Electronic supplementary material

Below is the link to the electronic supplementary material.

11274_2014_1685_MOESM1_ESM.tif

Supplementary Fig. S1. Effect of initial pH of broth medium adjusted by 1 N of both HCl and NaOH (a and b) or citrate phosphate buffer (c and d) on growth and production of MPA by AG101 (a and c) and LG109 (b and d) strain. Cultures were carried out at 25 °C and 120 rpm for 10 days in CDYE broth containing an inoculum size of 1 ml/50 ml medium. Data are shown as the mean ± SD of triplicate measurements from two independent experiments. (TIFF 2390 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ismaiel, A.A., Ahmed, A.S. & El-Sayed, ES.R. Optimization of submerged fermentation conditions for immunosuppressant mycophenolic acid production by Penicillium roqueforti isolated from blue-molded cheeses: enhanced production by ultraviolet and gamma irradiation. World J Microbiol Biotechnol 30, 2625–2638 (2014). https://doi.org/10.1007/s11274-014-1685-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11274-014-1685-1

Keywords

Search

Navigation