Production of clavulanic acid and cephamycin c by Streptomyces clavuligerus under different fed-batch conditions
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The effect of carbon source and feeding conditions on the production of clavulanic acid (CA) and cephamycin C (CephC) by Streptomyces clavuligerus was investigated. In fed-batch experiments performed with glycerol feeding, production of CA exceeded that of CephC, and reached 1022 mg.L-1. Highest CephC production (566.5 mg.L-1) was obtained in fed-batch cultivation with glycerol feeding. In fed-batch experiments performed with starch feeding, the production of CephC was in general higher than that of CA. A dissociation index (DI) was used to identify feeding conditions that favored production of CephC relative to CA. In all cultures with glycerol, DI values were less than unity, indicating higher production of CA compared to CephC. Conversely, in cultures fed with starch, the DI values obtained were greater than unity. However, no carbon source or feeding condition was able to completely dissociate the production of CA from that of CephC.
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Bellão et al. (2013) observed a higher maximum clavulanic acid concentration in fed-batch at 982.1 mg/L compared to 348.5 mg/L.
“A study by Bellão et al. (2013) observed a higher maximum clavulanic acid concentration in the latter method at 982.1 mg/L, as compared to 348.5 mg/L.”
From Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review (2016) · cites this paper as Bellão et al. (2013)
Table 2 reports a maximum clavulanic acid concentration of 982.1 mg/L for fed-batch run FB2, compared with 348.5 mg/L for batch control B1. However, 982.1 mg/L was not the highest fed-batch value in the study: the Results report 1002.6 mg/L for FB6. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe maximum clavulanic acid observed in glycerol-containing media was 348.5 mg/L, nearly two times higher than in starch-containing media (Bellão et al., 2013).
“Indeed the maximum amount of clavulanic acid observed in media containing glycerol was found to be 348.5 mg/L, nearly two times higher compared to media with starch as a sole carbon source (Bellão et al., 2013).”
From Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review (2016) · cites this paper as Bellão et al., 2013
The Batch Cultures section reports 348.5 mg/L of clavulanic acid with glycerol and 125.2 mg/L with starch. That is about 2.8 times, not nearly twice, the starch result. Table 2 also shows that 348.5 mg/L was the glycerol batch result, not the maximum across all glycerol-containing cultures; a glycerol-fed culture reached 1002.6 mg/L. (LLM, conf=0.94)
Experimental — accuracy not yet measuredComparing batch and fed-batch fermentation, fed-batch fermentation systems seemed to generate a higher yield of clavulanic acid.
“Comparing batch and fed-batch fermentation, fed-batch fermentation systems seemed to generate a higher yield of clavulanic acid (Chen et al., 2002; Neto et al., 2005; Bellão et al., 2013).”
From Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review (2016) · cites this paper as Bellão et al., 2013
Table 2 reports higher maximum clavulanic-acid concentrations in every fed-batch run than in the batch run using the same carbon source. But its product-yield coefficients (Y P/S) are mixed: several fed-batch runs have lower yields than their batch controls. The claim is supported if “yield” means the amount produced, but not as a general claim about product yield per unit substrate. The indexed copy does not give a specific page for Table 2. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCosta and Badino (2012) and Bellão et al. (2013) reported that utilization of glycerol in fed-batch fermentation systems resulted in a 1.2-2.8-fold increase in maximum clavulanic acid amount, depending on other factors such as temperature.
“Costa and Badino (2012) and Bellão et al. (2013) reported the utilization of glycerol in fed-batch fermentation systems resulted in a surge in the production of clavulanic acid (observed as a 1.2–2.8-fold increase in maximum clavulanic acid amount, depending on other factors such as temperature).”
From Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review (2016) · cites this paper as Bellão et al. (2013)
Table 2 reports maximum clavulanic acid concentrations of 348.5 mg/L in the glycerol batch culture and up to 982.1 mg/L in glycerol-fed cultures—approximately a 2.8-fold increase. The paper does not report a 1.2-fold increase, and its Culture Media and Experimental Conditions section says all cultivations were conducted at 28 °C, so it does not support temperature as a factor behind the range. (LLM, conf=0.88)
Experimental — accuracy not yet measuredA pH of 6.8 is favorable for obtaining high titers of CA in submerged cultures.
“Previous studies have shown that CA stability increases at slightly acidic pH values [10,11]; several authors found a pH of 6.8 as favorable for obtaining high titers of CA in submerged cultures [5,7,9,12,13,14,15,16].”
From Degradation Kinetics of Clavulanic Acid in Fermentation Broths at Low Temperatures (2019) · cites this paper as [7]
Basal media containing glycerol exhibited higher maximum amounts of clavulanic acid compared to starch.
“On the contrary, two studies reported a totally different observation—basal media containing glycerol exhibited higher maximum amounts of clavulanic acid as compared to starch (Saudagar and Singhal, 2007a; Bellão et al., 2013).”
From Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review (2016) · cites this paper as Bellão et al., 2013
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Research works printed but not linked: 11
- Bussari, B., Saudagar, P. S., Shaligram N. S., Survase S. A. and Singhal R. S., Production of cephamycin C by Streptomyces clavuligerus NT4 using solid-state fermentation. Journal of Industrial Microbiology and Biotechnology, 35, 49-58 (2008).
- Chen, K. C., Lin, Y., Tsai, C., Hsieh, C. and Houng, J., Optimization of glycerol feeding for clavulanic acid production by Streptomyces clavuligerus with glycerol feeding. Biotechnology Letters, 24, 455-458 (2002).
- Elson, S. M. and Oliver, R. S., Studies on the biosynthesis of clavulanic acid. I. Incorporation of 13 C-labelled precursor. Journal of Antibiotics, 31, 586-592 (1978).
- Fang, A. and Demain, A. L., Dependence of nitrogen- and phosphorus-regulation of β-lactam antibiotic Brazilian Journal of Chemical Engineering Vol. 30, No. 02, pp. 257 -266, April -June, 2013 production by Streptomyces clavuligerus on aeration level. Journal of Industrial Microbiology, 15, 407-410 (1995).
- Khaleeli, N., Li, R. F. and Townsend, C. A., Origin of the ß-lactam carbons in clavulanic acid from a unusual thiamine pyrophosphate mediated reac- tion. Journal of the American Chemical Society, 121, 9223-9224 (1999).
- Liras, P. and Martín, J. F., Assay methods for detection and quantification of antimicrobial me- tabolites produced by Streptomyces clavuligerus. In: Barredo, J. L. and Totowa, N. J., (Eds.), Methods in Biotechnology, Humana Press, v. 18, p. 149-163 (2005).
- Paradkar, A. S., Aidoo, K. A., Wong, A. and Jensen, S. E., Molecular analysis of a beta-lactam resistance gene encoded within the cephamycin gene cluster of Streptomyces clavuligerus. Journal of Bacteriology, 178, 6266-6274 (1996).
- Rollins, M. J., Jensen, S. E. and Westlake, D. W. S., Dissolved oxygen control of a maltose feed to batch fermentations of Streptomyces clavuligerus: Effect on cephamycin C biosynthesis. Biotech- nology Letters, 10, 295-300 (1988a).
- Rollins, M. J., Jensen, S. E. and Westlake, D. W. S., Effect of aeration on antibiotic production by Streptomyces clavuligerus. Journal of Industrial Microbiology, 3, 357-364 (1988b).
- Teodoro, J. C., Baptista-Neto, A., Araujo, M. L. G. C., Hokka, C. O. and Badino, A. C., Influence of glycerol and ornithine feeding on clavulanic acid production by Streptomyces clavuligerus. Brazilian Journal of Chemical Engineering, 27, 499-506 (2010).
- Yegneswaran, P. K., Gray, M. R. and Westlake, D. W. S., Effects of reduced oxygen on growth and antibiotic production in Streptomyces clavuligerus. Biotechnology Letters, 10, 479-484 (1988).
Cited by
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Ser, H.-L., Law, J. W.-F., Chaiyakunapruk, N., Jacob, S. A., Palanisamy, U. D., Chan, K.-G., Goh, B.-H., & Lee, L.-H. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00522 · Cited by 90 · see citing works
“On the contrary, two studies reported a totally different observation— basal media containing glycerol exhibited higher maximum amounts of clavulanic acid as compared to starch (Saudagar and Singhal, 2007a; Bellão et al., 2013).”
BackgroundResultInfluentialDegradation Kinetics of Clavulanic Acid in Fermentation Broths at Low Temperatures
Gómez-Ríos, D., Ramírez-Malule, H., Neubauer, P., Junne, S., & Ríos-Estepa, R. (2019) · Antibiotics · doi:10.3390/antibiotics8010006 · Cited by 17 · see citing works
- Authors
- Bellão, C., Antonio, T., Araujo, M. L. G. C., & Badino, A. C.
- Affiliations
- Universidade Federal de São Carlos (BR)
- Universidade Estadual Paulista (Unesp) (BR)
- Universidade Federal de São Carlos, Brazil
- Venue
- Brazilian Journal of Chemical Engineering
- Publisher
- FapUNIFESP (SciELO)
- Published
- 2013-06
- Volume
- 30
- Issue
- 2
- Pages
- 257-266
- ISSN
- 0104-6632 (ISSN-L)
- OpenAlex
- W2152598133
- Cited by
- 24
- References
- 0
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 3 · 2019: 4 · 2018: 3 · 2016: 4 · 2015: 2 · 2013: 1
- FWCI
- 1.71
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Brazilian Journal of Chemical Engineering (publishedVersion, cc-by-nc)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
- Acervo Digital da Universidade Estadual Paulista (Universidade Estadual Paulista) (submittedVersion, other-oa)
- Americanae (AECID Library) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, other-oa)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (11/23807-1, 05/55079-4)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Enzyme Production and Characterization
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Metabolism and Applications
- Keywords
- clavulanic acid, cephamycin C, Streptomyces clavuligerus, fed-batch fermentation, carbon source, glycerol feeding, secondary metabolite production
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