Abstract
Cephalosporins are currently the most widely used antibiotics in clinical practice. The main strain used for the industrial production cephalosporin C (CPC) is Acremonium chrysogenum. CPC has the advantages of possessing a broad antibacterial spectrum and strong antibacterial activity. However, the yield and titer of cephalosporins obtained from A. chrysogenum are much lower than penicillin, which is also a β-lactam antibiotic produced by Penicillium chrysogenum. Molecular biology research into A. chrysogenum has focused on gene editing technologies, multi-omics research which has provided information on the differences between high- and low-yield strains, and metabolic engineering involving different functional genetic modifications and hierarchical network regulation to understand strain characteristics. Furthermore, optimization of the fermentation process is also reviewed as it provides the optimal environment to realize the full potential of strains. Combining rational design to control the metabolic network, high-throughput screening to improve the efficiency of obtaining high-performance strains, and real-time detection and controlling in the fermentation process will become the focus of future research in A. chrysogenum. This minireview provides a holistic and in-depth analysis of high-yield mechanisms and improves our understanding of the industrial value of A. chrysogenum.
Key points
• Review of the advances in A. chrysogenum characteristics improvement and process optimization
• Elucidate the molecular bases of the mechanisms that control cephalosporin C biosynthesis and gene expression in A. chrysogenum
• The future development trend of A. chrysogenum to meet industrial needs
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References
Baltussen TJH, Zoll J, Verweij PE, Melchers WJG (2020) Molecular mechanisms of conidial germination in Aspergillus spp. Microbiol Mol Biol Rev 84(1):e00049-e119. https://doi.org/10.1128/MMBR.00049-19
Bartoshevich YuE, Zaslavskaya PL, Novak MJ, Yudina OD (1990) Acremonium chrysogenum differentiation and biosynthesis of cephalosporin. J Basic Microbiol 30(5):313–20. https://doi.org/10.1002/jobm.3620300503
Bibian ME, Perez-Sanchez A, Mejia A, Barrios-Gonzalez J (2020) Penicillin and cephalosporin biosyntheses are also regulated by reactive oxygen species. Appl Microbiol Biotechnol 104(4):1773–1783. https://doi.org/10.1007/s00253-019-10330-2
Bloemendal S, Löper D, Terfehr D, Kopke K, Kluge J, Teichert I, Kück U (2014) Tools for advanced and targeted genetic manipulation of the β-lactam antibiotic producer Acremonium chrysogenum. J Biotechnol 169:51–62. https://doi.org/10.1016/j.jbiotec.2013.10.036
Caicedo JC, Cooper S, Heigwer F, Warchal S, Qiu P, Molnar C, Vasilevich AS, Barry JD, Bansal HS, Kraus O, Wawer M, Paavolainen L, Herrmann MD, Rohban M, Hung J, Hennig H, Concannon J, Smith I, Clemons PA, Singh S, Rees P, Horvath P, Linington RG, Carpenter AE (2017) Data-analysis strategies for image-based cell profiling. Nat Methods 14(9):849–863. https://doi.org/10.1038/nmeth.4397
Cairns TC, Barthel L, Meyer V (2021) Something old, something new: challenges and developments in Aspergillus niger biotechnology. Essays Biochem 65(2):213–224. https://doi.org/10.1042/EBC20200139
Cairns TC, Feurstein C, Zheng X, Zheng P, Sun J, Meyer V (2019a) A quantitative image analysis pipeline for the characterization of filamentous fungal morphologies as a tool to uncover targets for morphology engineering: a case study using aplD in Aspergillus niger. Biotechnol Biofuels 12:149. https://doi.org/10.1186/s13068-019-1473-0
Cairns TC, Nai C, Meyer V (2018) How a fungus shapes biotechnology: 100 years of Aspergillus niger research. Fungal Biol Biotechnol 5:13. https://doi.org/10.1186/s40694-018-0054-5
Cairns TC, Zheng X, Feurstein C, Zheng P, Sun J, Meyer V (2022) A library of Aspergillus niger chassis strains for morphology engineering connects strain fitness and filamentous growth with submerged macromorphology. Front Bioeng Biotechnol 9:820088. https://doi.org/10.3389/fbioe.2021.820088
Cairns TC, Zheng XM, Zheng P, Sun JB, Meyer V (2019b) Moulding the mould: understanding and reprogramming filamentous fungal growth and morphogenesis for next generation cell factories. Biotechnol Biofuels 12:77. https://doi.org/10.1186/s13068-019-1400-4
Carlon-Andres I, Padilla-Parra S (2020) Quantitative FRET-FLIM-BlaM to assess the extent of HIV-1 fusion in live cells. Viruses 12(2):206. https://doi.org/10.3390/v12020206
Chen C, He J, Gao WY, Wei YM, Liu G (2019) Identification and characterization of an autophagy-related gene Acatg12 in Acremonium chrysogenum. Curr Microbiol 76(5):545–551. https://doi.org/10.1007/s00284-019-01650-7
Chen C, Liu JJ, Duan CB, Pan YY, Liu G (2020) Improvement of the CRISPR-Cas9 mediated gene disruption and large DNA fragment deletion based on a chimeric promoter in Acremonium chrysogenum. Fungal Genet Biol 134:103279. https://doi.org/10.1016/j.fgb.2019.103279
Chen GZ, Chu J (2019) Characterization of two polyketide synthases involved in sorbicillinoid biosynthesis by Acremonium chrysogenum using the CRISPR/Cas9 system. Appl Biochem Biotechnol 188(4):1134–1144. https://doi.org/10.1007/s12010-019-02960-z
Chen LJ, Xie XM (1987) Determination of cephalosporin C potency by auto-analyzer. Pharm industry 18(4):163–166. https://doi.org/10.16522/j.cnki.cjph.1987.04.007
Cruz-Ramon J, Fernandez FJ, Mejia A, Fierro F (2019) Electroporation of germinated conidia and young mycelium as an efficient transformation system for Acremonium chrysogenum. Folia Microbiol (Praha) 64(1):33–39. https://doi.org/10.1007/s12223-018-0625-0
Dai XJ (2008) Screening of cephalosporin C high-producing strain and study of fermentation process. Dissertation, Tianjin University
DeModena JA, Gutiérrez S, Velasco J, Fernández FJ, Fachini RA, Galazzo JL, Hughes DE, Martin JF (1993) The production of cephalosporin C by Acremonium chrysogenum is improved by the intracellular expression of a bacterial hemoglobin. Biotechnology (N Y) 11(8):926–929. https://doi.org/10.1038/nbt0893-926
Dreyer J, Eichhorn H, Friedlin E, Kürnsteiner H, Kück U (2007) A homologue of the Aspergillus velvet gene regulates both cephalosporin C biosynthesis and hyphal fragmentation in Acremonium chrysogenum. Appl Environ Microbiol 73(10):3412–3422. https://doi.org/10.1128/AEM.00129-07
Duan S, Yuan G, Zhao Y, Li H, Ni W, Sang M, Liu L, Shi Z (2012) Enhanced cephalosporin C production with a combinational ammonium sulfate and DO-Stat based soybean oil feeding strategy. Biochem Engineering J 61:1–10. https://doi.org/10.1016/j.bej.2011.11.011
Du ST (2011) Study on the mutation breeding of protoplasts of cephalosporin C producingstrain Cephalosporium acremonium HC-4. Dissertation, Agricultural University of Hebei
Duan SB, Yuan GQ, Zhao YL, Ni WJ, Luo HZ, Shi ZP, Liu F (2013) Simulation of computational fluid dynamics and comparison of cephalosporin C fermentation performance with different impeller combinations. Korean J Chem Eng 30(5):1097–1104. https://doi.org/10.1007/s11814-013-0010-2
Dumina MV, Zhgun AA, Novak MI, Domratcheva AG, Petukhov DV, Dzhavakhiya VV, Eldarov MA, Bartoshevitch IE (2014) Comparative gene expression profiling reveals key changes in expression levels of cephalosporin C biosynthesis and transport genes between low and high-producing strains of Acremonium chrysogenum. World J Microbiol Biotechno 30(11):2933–2941. https://doi.org/10.1007/s11274-014-1721-1
Ellaiah P, Adinarayana K, Chand GM, Subramanyam GSV, Srinivasulu B (2002) Strain improvement studies for cephalosporin C production by Cephalosporium acremonium. Pharmazie 57(7):489–490. https://doi.org/10.2307/3802648
El-bashiti TA (2018) Production of cephalosporin C from Acremonium chrysogenum, and its antimicrobial activity against some pathogenic bacteria Pharm and Chem J 4(2): 19–23
Etxebeste O, Espeso EA (2020) Aspergillus nidulans in the post-genomic era: a top-model filamentous fungus for the study of signaling and homeostasis mechanisms. Int Microbiol 23(1):5–22. https://doi.org/10.1007/s10123-019-00064-6
Fiedler MRM, Cairns TC, Koch O, Kubisch C, Meyer V (2018) Conditional expression of the small GTPase arfA impacts secretion, morphology, growth, and actin ring position in Aspergillus niger. Front Microbiol 9:878. https://doi.org/10.3389/fmicb.2018.00878
Newton GG, Abraham EP (1954) Degradation, structure and some derivatives of cephalosporin N. Biochem J 58(1):103–11. https://doi.org/10.1042/bj0580103
Gonçalves AP, Heller J, Daskalov A, Videira A, Glass NL (2017) Regulated forms of cell death in fungi. Front Microbiol 8:1837. https://doi.org/10.3389/fmicb.2017.01837
Guan FF, Pan YY, Li JY, Liu G (2017) A GATA-type transcription factor AcAREB for nitrogen metabolism is involved in regulation of cephalosporin biosynthesis in Acremonium chrysogenum. Sci China Life Sci 60(9):958–967. https://doi.org/10.1007/s11427-017-9118-9
Gutiérrez S, Velasco J, Marcos AT, Fernández FJ, Fierro F, Barredo JL, Díez B, Martín JF (1997) Expression of the cefG gene is limiting for cephalosporin biosynthesis in Acremonium chrysogenum. Appl Microbiol Biotechnol 48(5):606–614. https://doi.org/10.1007/s002530051103
Gutiérrez-Medina B, Vázquez-Villa A (2021) Visualizing three-dimensional fungal growth using light sheet fluorescence microscopy. Fungal Genet Biol 150:103549. https://doi.org/10.1016/j.fgb.2021.103549
Guzmán-Chávez F, Salo O, Nygård Y, Lankhorst PP, Bovenberg RAL, Driessen AJM (2017) Mechanism and regulation of sorbicillin biosynthesis by Penicillium chrysogenum. Microb Biotechnol 10(4):958–968. https://doi.org/10.1111/1751-7915.12736
Han S, Liu Y, Xie LP, Zhu BQ, Hu YJ (2016) Comparative expression profiling of genes involved in primary metabolism in high-yield and wild-type strains of Acremonium chrysogenum. Antonie Van Leeuwenhoek 109(3):357–369. https://doi.org/10.1007/s10482-015-0638-5
Hijarrubia MJ, Aparicio JF, Casqueiro J, Martín JF (2001) Characterization of the lys2 gene of Acremonium chrysogenum encoding a functional alpha-aminoadipate activating and reducing enzyme. Mol Gen Genet 264(6):755–762. https://doi.org/10.1007/s004380000364
Hoff B, Schmitt EK, Kück U (2005) CPCR1, but not its interacting transcription factor AcFKH1, controls fungal arthrospore formation in Acremonium chrysogenum. Mol Microbiol 56(5):1220–1233. https://doi.org/10.1111/j.1365-2958.2005.04626.x
Hou L, Liu L, Zhang HF, Zhang L, Zhang L, Zhang J, Gao Q, Wang DP (2018) Functional analysis of the mitochondrial alternative oxidase gene (aox1) from Aspergillus niger CGMCC 10142 and its effects on citric acid production. Appl Microbiol Biotechnol 102(18):7981–7995. https://doi.org/10.1007/s00253-018-9197-9
Hu LQ, Liu RQ, Ma Z, Yu T, Li ZY, Zou YQ, Yuan C, Chen FF, Xie HX (2021) Specific detection of IMP-1 β-lactamase activity using a trans cephalosporin-based fluorogenic probe. Chem Commun (Camb) 57(99):13586–13589. https://doi.org/10.1039/d1cc05955f
Hu PJ, Wang Y, Zhou J, Pan YY, Liu G (2015) AcstuA, which encodes an APSES transcription regulator, is involved in conidiation, cephalosporin biosynthesis and cell wall integrity of Acremonium chrysogenum. Fungal Genet Biol 83:26–40. https://doi.org/10.1016/j.fgb.2015.08.003
Hu Y, Zhu B (2016) Study on genetic engineering of Acremonium chrysogenum, the cephalosporin C producer. Synth Syst Biotechnol 1(3):143–149. https://doi.org/10.1016/j.synbio.2016.09.002
Hua E, Zhang Y, Yun K, Pan W, Liu Y, Li S, Wang Y, Tu R, Wang M (2022) Whole-cell biosensor and producer co-cultivation-based microfludic platform for screening Saccharopolyspora erythraea with hyper erythromycin production. ACS Synth Biol. https://doi.org/10.1021/acssynbio.2c00102
Iacovelli R, Mózsik L, Bovenberg RAL, Driessen AJM (2021) Identification of a conserved N-terminal domain in the first module of ACV synthetases. Microbiologyopen 10(1):e1145. https://doi.org/10.1002/mbo3.1145
Jami MS, Barreiro C, García-Estrada C, Martín JF (2010) Proteome analysis of the penicillin producer Penicillium chrysogenum: characterization of protein changes during the industrial strain improvement. Mol Cell Proteomics 9(6):1182–1198. https://doi.org/10.1074/mcp.M900327-MCP200
Janus D, Hoff B, Hofmann E, Kück U (2007) An efficient fungal RNA-silencing system using the DsRed reporter gene. Appl Environ Microbiol 73(3):962–970. https://doi.org/10.1128/AEM.02127-06
Jiang CM, Lv GB, Tu YY, Cheng XJ, Duan YT, Zeng B, He B (2021) Applications of CRISPR/Cas9 in the synthesis of secondary metabolites in filamentous fungi. Front Microbiol 12:638096. https://doi.org/10.3389/fmicb.2021.638096
Karaffa L, Sándor E, Fekete E, Kozma J, Szentirmai A, Pócsi I (2003) Stimulation of the cyanide-resistant alternative respiratory pathway by oxygen in Acremonium chrysogenum correlates with the size of the intracellular peroxide pool. Can J Microbiol 49(3):216–220. https://doi.org/10.1139/w03-029
Karahalil E, Coban HB, Turhan I (2019) A current approach to the control of filamentous fungal growth in media: microparticle enhanced cultivation technique. Crit Rev Biotechnol 39(2):192–201. https://doi.org/10.1080/07388551.2018.1531821
Kaur B, Punekar NS (2019) Autophagy is important to the acidogenic metabolism of Aspergillus niger. PLoS ONE 14(10):e0223895. https://doi.org/10.1371/journal.pone.0223895
Kim HS, Kim JO, Lee JE, Park KG, Lee HK, Kim SY, Min SJ, Kim J, Park YJ (2019) Performance of a novel fluorogenic assay for detection of carbapenemase-producing enterobacteriaceae from bacterial colonies and directly from positive blood cultures. J Clin Microbiol 58(1):e01026-e1119. https://doi.org/10.1128/JCM.01026-19
Klein EY, Boeckel TPV, Martinez EM, Pant S, Gandra S, Levin S A, Goossens H, Laxminarayan R (2018) Global increase and geographic convergence in antibiotic consumption between 2000 and 2015. Proc Natl Acad Sci U S A 115(15):E3463–E3470. https://doi.org/10.1073/pnas.1717295115
Kluge J, Kück U (2018) AcAxl2 and AcMst1 regulate arthrospore development and stress resistance in the cephalosporin C producer Acremonium chrysogenum. Curr Genet 64(3):713–727. https://doi.org/10.1007/s00294-017-0790-8
Kluge J, Terfehr D, Kück U (2018) Inducible promoters and functional genomic approaches for the genetic engineering of filamentous fungi. Appl Microbiol Biotechnol 102(15):6357–6372. https://doi.org/10.1007/s00253-018-9115-1
Kosalková K, Marcos AT, Martín JF (2001) A moderate amplification of the mecB gene encoding cystathionine-γ-lyase stimulates cephalosporin biosynthesis in Acremonium chrysogenum. J Industrial Microbiol and Biotechnol 27(4):252–258. https://doi.org/10.1038/sj.jim.7000192
Lee JH, Yoo HY, Yang X, Kim DS, Lee JH, Lee SK, Han SO, Kim SW (2017) Utilization of algal sugars and glycerol for enhanced cephalosporin C production by Acremonium chrysogenum M35. Lett Appl Microbiol 64(1):66–72. https://doi.org/10.1111/lam.12684
Leeuwe TMV, Wattjes J, Niehues A, Forn-Cuní G, Geoffrion N, Mélida H, Arentshorst M, Molina A, Tsang A, Meijer AH, Moerschbacher BM, Punt PJ, Ram AFJ (2020) A seven-membered cell wall related transglycosylase gene family in Aspergillus niger is relevant for cell wall integrity in cell wall mutants with reduced α-glucan or galactomannan. Cell Surf 6:100039. https://doi.org/10.1016/j.tcsw.2020.100039
Li (2011) Selection of high Cephalosporin C producing Cephalosporium acremonium and optimization of its production medium. Dissertation, Zhejiang University
Li HH, Hu PJ, Wang Y, Pan YY, Liu G (2018) Enhancing the production of cephalosporin C through modulating the autophagic process of Acremonium chrysogenum. Microb Cell Fact 17(1):175. https://doi.org/10.1186/s12934-018-1021-9
Li JH, Yang YM, Chu J, Huang MZ, Li L, Zhang XC, Wang YH, Zhuang YP, Zhang SL (2010) Quantitative metabolic flux analysis revealed uneconomical utilization of ATP and NADPH in Acremonium chrysogenum fed with soybean oil. Bioprocess Biosystems Eng 33(9):1119–1129. https://doi.org/10.1007/s00449-010-0439-1
Li JY, Pan YY, Liu G (2013) Disruption of the nitrogen regulatory gene AcareA in Acremonium chrysogenum leads to reduction of cephalosporin production and repression of nitrogen metabolism. Fungal Genet Biol 61:69–79. https://doi.org/10.1016/j.fgb.2013.10.006
Li YY (2017) High throuughput screening of high-yield cephalosporin C production strain and measurement of the oil contents of bioprocessess using low-field NMR. Dissertation, East China University of Science and Technology
Lima LM, Silva BNMD, Barbosa G, Barreiro EJ (2020) β-lactam antibiotics: an overview from a medicinal chemistry perspective. Eur J Med Chem 208:112829. https://doi.org/10.1016/j.ejmech.2020.112829
Liu JJ, Gao WY, Pan YY, Liu G (2018) Metabolic engineering of Acremonium chrysogenum for improving cephalosporin C production independent of methionine stimulation. Microb Cell Fact 17(1):87. https://doi.org/10.1186/s12934-018-0936-5
Liu JJ, Hao TC, Hu PJ, Pan YY, Jiang XJ, Liu G (2017) Functional analysis of the selective autophagy related gene Acatg11 in Acremonium chrysogenum. Fungal Genet Biol 107:67–76. https://doi.org/10.1016/j.fgb.2017.08.006
Liu JJ, Liu G (2016) Advances in the regulation of cephalosporin C biosynthesis-a review. Acta Microbiol Sin 56(3):461–470. https://doi.org/10.13343/j.cnki.wsxb.20150535
Liu L, Chen Z, Tian XW, Chu J (2022) Knockout and functional analysis of BSSS-related genes in Acremonium chrysogenum by novel episomal expression vector containing Cas9 and AMA1. Biotechnol Lett. https://doi.org/10.1007/s10529-022-03255-w
Liu L, Long LK, An Y, Yang J, Xu XX, Hu CH, Liu G (2013) The thioredoxin reductase-encoding gene ActrxR1 is involved in the cephalosporin C production of Acremonium chrysogenum in methionine-supplemented medium. Appl Microbiol Biotechnol 97(6):2551–2562. https://doi.org/10.1007/s00253-012-4368-6
Liu Y, Xie LP, Gong GH, Zhang W, Zhu BQ, Hu YJ (2014) De novo comparative transcriptome analysis of Acremonium chrysogenum: high-yield and wild-type strains of cephalosporin C Producer. PLoS ONE 9(8):e104542. https://doi.org/10.1371/journal.pone.0104542
Long LK, Wang YL, Yang J, Xu XX, Liu G (2013) A septation related gene AcsepH in Acremonium chrysogenum is involved in the cellular differentiation and cephalosporin production. Fungal Genet Biol 50:11–20. https://doi.org/10.1016/j.fgb.2012.11.002
Long LK, Yang J, An Y, Liu G (2012) Disruption of a glutathione reductase encoding gene in Acremonium chrysogenum leads to reduction of its growth, cephalosporin production and antioxidative ability which is recovered by exogenous methionine. Fungal Genet Biol 49(2):114–122. https://doi.org/10.1016/j.fgb.2011.12.004
López-Calleja AC, Cuadra T, Barrios-González J, Fierro F, Fernández FJ (2012) Solid-state and submerged fermentations show different gene expression profiles in cephalosporin C production by Acremonium chrysogenum. J Mol Microbiol Biotechnol 22(2):126–34. https://doi.org/10.1159/000338987
Lu H, Cao W, Liu X, Sui Y, Ouyang L, Xia J, Huang M, Zhuang Y, Zhang S, Noorman H, Chu J (2018) Multi-omics integrative analysis with genome-scale metabolic model simulation reveals global cellular adaptation of Aspergillus niger under industrial enzyme production condition. Sci Rep 8(1):14404. https://doi.org/10.1038/s41598-018-32341-1
Lu H, Cao W, Ouyang L, Xia J, Huang M, Chu J, Zhuang Y, Zhang S, Noorman H (2017) Comprehensive reconstruction and in silico analysis of Aspergillus niger genome-scale metabolic network model that accounts for 1210 ORFs. Biotechnol Bioeng 114(3):685–695. https://doi.org/10.1002/bit.26195
Martin JF, Demain AL (2002) Unraveling the methionine–cephalosporin puzzle in Acremonium chrysogenum. Trends Biotechnol 20(12):502–507. https://doi.org/10.1016/s0167-7799(02)02070-x
Martin JF (2020) Transport systems, intracellular traffic of intermediates and secretion of beta-lactam antibiotics in fungi. Fungal Biol Biotechnol 7:6. https://doi.org/10.1186/s40694-020-00096-y
Martínez Y, Li X, Liu G, Bin P, Yan W, Más D, Valdivié M, Hu CA, Ren W, Yin Y (2017) The role of methionine on metabolism, oxidative stress, and diseases. Amino Acids 49(12):2091–2098. https://doi.org/10.1007/s00726-017-2494-2
Meng GQ, Zhao L, Dai XJ, Li YZ, Liu XL (2010) Rational screening of cephalosporin C high yielding producing strains. Chin J Antibiotics 36(12):889–894. https://doi.org/10.1007/s11606-010-1494-7
Meyer V, Cairns T, Barthel L, King R, Kunz P, Schmideder S, Müller H, Briesen H, Dinius A, Krull R (2021) Understanding and controlling filamentous growth of fungal cell factories: novel tools and opportunities for targeted morphology engineering. Fungal Biol Biotechnol 8(1):8. https://doi.org/10.1186/s40694-021-00115-6
Molnár ÁP, Németh Z, Kolláth IS, Fekete E, Flipphi M, Ág N, Soós Á, Kovács B, Sándor E, Kubicek CP, Karaffa L (2018) High oxygen tension increases itaconic acid accumulation, glucose consumption, and the expression and activity of alternative oxidase in Aspergillus terreus. Appl Microbiol Biotechnol 102(20):8799–8808. https://doi.org/10.1007/s00253-018-9325-6
Mózsik L, Pohl C, Meyer V, Bovenberg RAL, Nygård Y, Driessen AJM (2021) Modular synthetic biologytoolkit for filamentous fungi. ACS Synth Biol 10(11):2850–2861. https://doi.org/10.1021/acssynbio.1c00260
Müller H, Barthel L, Schmideder S, Schütze T, Meyer V, Briesen H (2022) From spores to fungal pellets: a new high throughput image analysis highlights the structural development of Aspergillus niger. Biotechnol Bioeng. https://doi.org/10.1002/bit.28124
Nainu F, Permana AD, Djide NJN, Anjani QK, Utami RN, Rumata NR, Zhang J, Emran TB, Simal-Gandara J (2021) Pharmaceutical approaches on antimicrobial resistance: prospects and challenges. Antibiotics (Basel) 10(8):981. https://doi.org/10.3390/antibiotics10080981
Niu LJ, Zhnag T, Dang JN, Zhang BX (2021) Mutation breeding and fermentation application of cephalosporin C-producing strain Cephalosporium acremonium. Chemi Bioeng 38(10):57–61. https://doi.org/10.3969/j.issn.1672-5425.2021.10.012
Phelan RM, Ostermeier M, Townsend CA (2009) Design and synthesis of a beta-lactamase activated 5-fluorouracil prodrug. Bioorg Med Chem Lett 19(4):1261–3. https://doi.org/10.1016/j.bmcl.2008.12.057
Pollack JK, Harris SD, Marten MR (2009) Autophagy in filamentous fungi. Fungal Genet Biol 46(1):1–8. https://doi.org/10.1016/j.fgb.2008.10.010
Porto A, Rolfe S, Maga AM (2021) ALPACA: a fast and accurate computer vision approach for automated landmarking of three-dimensional biological structures. Methods Ecol Evol 12(11):2129–2144. https://doi.org/10.1111/2041-210X.13689
Rageh AH, El-Shaboury SR, Saleh GA, Mohamed FA (2010) Spectophotometric method for determination of certain cephalosporins using 4-chloro-7-nitrobenzo-2-oxa-1, 3-diazole (NBD-Cl). Nat Sci 2(8):828–840. https://doi.org/10.4236/ns.2010.28104
Ren L (2013) Screening of cephalosporin C high-producing strain and study of fermentation technology. Dissertation, Hebei University of Science and Technology
Salo O, Guzmán-Chávez F, Ries MI, Lankhorst PP, Bovenberg RAL, Vreeken RJ, Driessen AJM (2016) Identification of a polyketide synthase involved in sorbicillin biosynthesis by Penicillium chrysogenum. Appl Environ Microbiol 82(13):3971–3978. https://doi.org/10.1128/AEM.00350-16
Sang QH, liang JL, Song AG, Bai FJ, Shi N, Jiang T (2007) Study of microwave mutagenesis on selection ofcephalosporin C production strain-Cephalosporium Acremonium. Qilu Pham Aff 6(9): 615–616
Senter PD, Springer CJ (2001) Selective activation of anticancer prodrugs by monoclonal antibody-enzyme conjugates. Adv Drug Deliv Rev 53(3):247–64. https://doi.org/10.1016/s0169-409x(01)00206-x
Schmitt EK, Bunse A, Janus D, Hoff B, Friedlin E, Kurnsteiner H, Kück U (2004a) Winged helix transcription factor CPCR1 is involved in regulation of beta-lactam biosynthesis in the fungus Acremonium chrysogenum. Eukaryot Cell 3(1):121–134. https://doi.org/10.1128/EC.3.1.121-134.2004
Schmitt EK, Hoff B, Kück U (2004b) AcFKH1, a novel member of the forkhead family, associates with the RFX transcription factor CPCR1 in the cephalosporin C-producing fungus Acremonium chrysogenum. Gene 342(2):269–281. https://doi.org/10.1016/j.gene.2004.08.002
Schmitt EK, Hoff B, Kück U (2004c) Regulation of cephalosporin biosynthesis. Adv Biochem Eng Biotechnol 88:1–43. https://doi.org/10.1007/b99256
Schmitt EK, Kempken R, Kück U (2001) Functional analysis of promoter sequences of cephalosporin C biosynthesis genes from Acremonium chrysogenum: specific DNA-protein interactions and characterization of the transcription factor PACC. Mol Genet Genomics 265(3):508–518. https://doi.org/10.1007/s004380000439
Shahidzadeh H, Labbeiki G, Attar H (2017) Enhanced fermentative production of Cephalosporin C by magnetite nanoparticles in culture of Acremonium chrysogenum. Iet Nanobiotechnol 11(6):644–649. https://doi.org/10.1049/iet-nbt.2016.0155
Son YE, Park HS (2019) Conserved roles of monA in fungal growth and development in Aspergillus species. Mycobiology 47(4):457–465. https://doi.org/10.1080/12298093.2019.1677380
Song ZH, Pan J, Xie LP, Gong GH, Han S, Zhang W, Hu YJ (2017) Expression, purification, and activity of ActhiS, a thiazole biosynthesis enzyme from Acremonium chrysogenum. Biochem (Mosc) 82(7):852–860. https://doi.org/10.1134/S0006297917070112
Srivastava P, Kundu S (1999) Studies on cephalosporin-C production in an air lift reactor using different growth modes of Cephalosporium acremonium. Process Biochem 34(4):329–333. https://doi.org/10.1016/S0032-9592(98)00059-4
Sun R, Xu H, Feng Y, Hou X, Zhu T, Che Q, Pfeifer B, Zhang G, Li D (2021) An efficient marker recycling system for sequential gene deletion in a deep sea-derived fungus Acremonium sp. HDN16–126. Synth Syst Biotechnol 6(2):127–133. https://doi.org/10.1016/j.synbio.2021.05.001
Tan J, Chu J, Hao YY, Guo YX, Zhuang YP, Zhang SL (2013) High-throughput system for screening of Cephalosporin C high-yield strain by 48-deep-well microtiter plates. Appl Biochem Biotechnol 169(5):1683–1695. https://doi.org/10.1007/s12010-013-0095-4
Tan Q, Qiu J, Luo X, Zhang Y, Liu Y, Chen Y, Yuan J, Liao W (2018) Progress in one-pot bioconversion of cephalosporin C to 7-aminocephalosporanic acid. Curr Pharm Biotechnol 19(1):30–42. https://doi.org/10.2174/1389201019666180509093956
Teijeira F, Ullán RV, Guerra SM, García-Estrada C, Vaca I, Martín JF (2009) The transporter CefM involved in translocation of biosynthetic intermediates is essential for cephalosporin production. Biochem J 418:113–124. https://doi.org/10.1042/BJ20081180
Terfehr D, Dahlmann TA, Kück U (2017) Transcriptome analysis of the two unrelated fungal β-lactam producers Acremonium chrysogenum and Penicillium chrysogenum: velvet-regulated genes are major targets during conventional strain improvement programs. BMC Genomics 18(1):272. https://doi.org/10.1186/s12864-017-3663-0
Terfehr D, Dahlmann TA, Specht T, Zadra I, Kürnsteiner H, Kück U (2014) Genome sequence and annotation of Acremonium chrysogenum, producer of the β-Lactam antibiotic cephalosporin C. Genome Announc 2(5):e00948-e1014. https://doi.org/10.1128/genomeA.00948-14
Terfehr D, Kück U (2017) Deactivation of the autotrophic sulfate assimilation pathway substantially reduces high-level β-lactam antibiotic biosynthesis and arthrospore formation in a production strain from Acremonium chrysogenum. Microbiology (reading) 163(6):817–828. https://doi.org/10.1099/mic.0.000474
Tollnick C, Seidel G, Beyer M, Schügerl K (2004) Investigations of the production of cephalosporin C by Acremonium chrysogenum. Adv Biochem Eng Biotechnol 86:1–45. https://doi.org/10.1007/b12439
Pérez-Pérez WD, Carrasco-Navarro U, García-Estrada C, Kosalková K, Gutiérrez-Ruíz MC, Barrios-González J, Fierro F (2022) bZIP transcription factors PcYap1 and PcRsmA link oxidative stress response to secondary metabolism and development in Penicillium chrysogenum. Microb Cell Fact 21(1):50. https://doi.org/10.1186/s12934-022-01765-w
Ullán RV, Godio RP, Teijeira F, Vaca I, García-Estrada C, Feltrer R, Kosalkova K, Martín JF (2008a) RNA-silencing in Penicillium chrysogenum and Acremonium chrysogenum: validation studies using beta-lactam genes expression. J Microbiol Methods 75(2):209–218. https://doi.org/10.1016/j.mimet.2008.06.001
Ullán RV, Liu G, Casqueiro J, Gutiérrez S, Bañuelos O, Martín JF (2002) The cefT gene of Acremonium chrysogenum C10 encodes a putative multidrug efflux pump protein that significantly increases cephalosporin C production. Mol Genet Genomics 267(5):673–683. https://doi.org/10.1007/s00438-002-0702-5
Ullán RV, Teijeira F, Guerra SM, Vaca I, Martín JF (2010) Characterization of a novel peroxisome membrane protein essential for conversion of isopenicillin N into cephalosporin C. Biochem J 432(2):227–236. https://doi.org/10.1042/BJ20100827
Ullán RV, Teijeira F, Martín JF (2008b) Expression of the Acremonium chrysogenum cefT gene in Penicillum chrysogenum indicates that it encodes an hydrophilic beta-lactam transporter. Curr Genet 54(3):153–161. https://doi.org/10.1007/s00294-008-0207-9
Veiter L, Rajamanickam V, Herwig C (2018) The filamentous fungal pellet-relationship between morphology and productivity. Appl Microbiol Biotechnol 102(7):2997–3006. https://doi.org/10.1007/s00253-018-8818-7
Velasco J, Gutiérrez S, Casqueiro J, Fierro F, Campoy S, Martín JF (2001) Cloning and characterization of the gene cahB encoding a cephalosporin C acetylhydrolase from Acremonium chrysogenum. Appl Microbiol and Biotechnol 57:350–356. https://doi.org/10.1007/s002530100769
Wang G, Haringa C, Tang W, Noorman H, Chu J, Zhuang YP, Zhang SL (2020a) Coupled metabolic-hydrodynamic modeling enabling rational scale-up of industrial bioprocesses. Biotechnol Bioeng 117(3):844–867. https://doi.org/10.1002/bit.27243
Wang G, Haringa C, Noorman H, Chu J, Zhuang Y (2020) Developing a computational framework to advance bioprocess Scale-Up. Trends Biotechnol 38(8):846–856. https://doi.org/10.1016/j.tibtech.2020.01.009
Wang ZJ. Wang XH, Liu C, Hang HF, Chu J, Guo MJ, Zhuang YP (2021) Method for increasing penicillin fermentation production unit. China Patent: CN113388658A
Wang HT, Pan YY, Hu PJ, Zhu YX, Li JY, Jiang XJ, Liu G (2014) The autophagy-related gene Acatg1 is involved in conidiation and cephalosporin production in Acremonium chrysogenum. Fungal Genet Biol 69:65–74. https://doi.org/10.1016/j.fgb.2014.06.004
Xie J, Mu R, Fang M, Cheng Y, Senchyna F, Moreno A, Banaei N, Rao J (2021) A dual-caged resorufin probe for rapid screening of infections resistant to lactam antibiotics. Chem Sci 12(26):9153–9161. https://doi.org/10.1039/d1sc01471d
Xu W, Zhu CB, Zhu BQ (2005) An efficient and stable method for the transformation of heterogeneous genes into Cephalosporium acremonium mediated by Agrobacterium tumefaciens. J Microbiol and Biotechnol 15(4):683–688
Xu Y, Liu L, Chen Z, Tian XW, Chu J (2021) The arthrospore-related gene Acaxl2 is involved in cephalosporin C production in industrial Acremonium chrysogenum by the regulatory factors AcFKH1 and CPCR1. J Biotechnol 347:26–39. https://doi.org/10.1016/j.jbiotec.2021.12.011
Yang DM, Su WC, Jiang YY, Gao SS, Li XY, Qu G, Sun ZT (2022) Biosynthesis of β-lactam nuclei in yeast. Metab Eng 72:56–65. https://doi.org/10.1016/j.ymben.2022.02.005
Yang S, Zhao CY, Ouyang LM, Ju C, Zhang SL (2016) Optimization of protoplast preparation and regeneration conditions of Acremonium chrysogenum. Chin J Pharm 47(6):687–691. https://doi.org/10.16522/j.cnki.cjph.2016.06.005
Yang YM, Xia JY, Li JH, Chu J, Li L, Wang YH, Zhuang YP, Zhang SL (2012) A novel impeller configuration to improve fungal physiology performance and energy conservation for cephalosporin C production. J Biotechnol 161(3):250–256. https://doi.org/10.1016/j.jbiotec.2012.07.007
Zheng R, Zhu CB, Zhao WJ, Zhu BQ (1998) Improvement in protoplast preparation and regeneration of Cephalosporium Acreminium. Chin J Pharm 29(4):156–159. https://doi.org/10.16522/j.cnki.cjph.1998.04.004
Zhgun A, Dumina M, Valiakhmetov A, Eldarov M (2020) The critical role of plasma membrane H+-ATPase activity in cephalosporin C biosynthesis of Acremonium chrysogenum. PLoS One 15(8):e0238452. https://doi.org/10.1371/journal.pone.0238452
Zhgun AA, Eldarov MA (2021) Polyamines upregulate cephalosporin C production and expression of β-lactam biosynthetic genes in high-yielding Acremonium chrysogenum strain. Molecules 26(21):6636. https://doi.org/10.3390/molecules26216636
Zhgun AA, Ivanova MA, Domracheva AG, Novak MI, Elidarov MA, Skryabin KG, Bartoshevich IE (2008) Genetic transformation of the mycelium fungi Acremonium chrysogenum. Prikl Biokhim Mikrobiol 44(6):663–670
Zhou W, Holzhauer-Rieger K, Dors M, Schügerl K (1992) Influence of dissolved oxygen concentration on the biosynthesis of cephalosporin C. Enzyme Microb Technol 14(10):848–854. https://doi.org/10.1016/0141-0229(92)90103-u
Ziemons S, Koutsantas K, Becker K, Dahlmann T, Kück U (2017) Penicillin production in industrial strain Penicillium chrysogenum P2niaD18 is not dependent on the copy number of biosynthesis genes. BMC Biotechnol 17(1):16. https://doi.org/10.1186/s12896-017-0335-8
Zlokarnik G, Negulescu PA, Knapp TE, Mere L, Burres N, Feng L, Whitney M, Roemer K, Tsien RY (1998) Quantitation of transcription and clonal selection of single living cells with beta-lactamase as reporter. Science 279(5347):84–88. https://doi.org/10.1126/science.279.5347.84
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Liu L, Chen Z, and Liu WY designed the structure of this review. Ke X, Chu J, and Tian XW revised the manuscript. Liu L wrote the manuscript. All the authors read and approved the final manuscript.
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Liu, L., Chen, Z., Liu, W. et al. Cephalosporin C biosynthesis and fermentation in Acremonium chrysogenum. Appl Microbiol Biotechnol 106, 6413–6426 (2022). https://doi.org/10.1007/s00253-022-12181-w
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DOI: https://doi.org/10.1007/s00253-022-12181-w