An Approach to Strain Improvement and Enhanced Production of Clavulanic Acid in Streptomyces clavuligerus
Abstract
To develop a strategy for improved production of clavulanic acid (CA), we investigated the effect of using oils on cell growth and CA production during the fermentation of Streptomyces clavuligerus NRRL 3585. In this analysis, triolein, whose fatty acid is oleic acid only, was the best oil source for CA production, but free fatty acids generated from the hydrolysis of oils in a culture broth negatively impacted CA production and cell growth. Hence, we screened for mutants that were resistant to high concentrations of oleic acid. From this screen we identified a mutant S. clavuligerus, OL13, that had a minimum inhibitory concentration (MIC) to oleic acid of 2.1 g/l, much higher than that of S. clavuligerus NRRL 3585, at 0.4 g/l. Not only was cell growth improved, but maximum CA production, at 1,950 mg/l, was approximately 2.0-fold higher than that of the parent strain.
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The highest clavulanic acid production in Kim et al. (2009) was observed in media containing triolein at 989 mg/L.
“The highest clavulanic acid production reported in the same study was observed in media containing triolein (which is a major constituent of palm oil) at 989 mg/L.”
From Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review (2016) · cites this paper as Kim et al. (2009)
The Discussion reports a clavulanic acid titer of 989 mg/L with triolein, supporting that measurement. But the section “Fermentation profile of an oleic acid resistant mutant” reports a higher maximum of 1,950 mg/L for mutant OL13 grown in triolein-supplemented medium, so 989 mg/L was not the highest production reported in the study. (LLM, conf=0.88)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredKim et al. (2009) reported maximum clavulanic acid production of 700 mg/mL in media supplemented with palm oil.
“A more recent study in 2009 by Kim et al. (2009) reported maximum clavulanic acid production of 700 mg/mL in media supplemented with palm oil, an intermediate value as compared to other oil sources.”
From Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review (2016) · cites this paper as Kim et al. (2009)
The ‘Effects of oils on the production of CA’ section (page unavailable) reports that palm oil stimulated production relative to some tested oils, but it does not report 700 mg/mL for palm oil. It identifies 989 mg/L with triolein as the highest production among the oils tested; the claimed value and units are unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measured
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Cites
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Research works printed but not linked: 6
- Saudagar, P. S., Survase, S. A., and Singhal, R. S., Clavulanic acid: a review. Biotechnol. Adv., 26, 335-351 (2008).
- Stowell, J. D., Beardsmore, A. J., Keevil, C. W., and Woodward, J. R., Oxford University Press, New York, pp. 139-159 (1985).
- Vandamme, E. J., Marcel Dekker, New York, pp. 225-235 (1984).
- Korbekandi, H., Hojjati, Z., Abedi, D., Pourhosein, M., and Darkhal, P., Overproduction of clavulanic acid by UV muta- genesis of Streptomyces clavuligerus. J. Biotechnol., 131, S187 (2007).
- Kieser, T., Bibb, M. J., Buttner, M. J., Chater, K. F., and Hopwood, D. A., Mutagenesis of Streptomyces by irradiation or chemicals. In ''Practical Streptomyces Genetics,'' The John Innes Foundation, Norwich, pp. 99-108 (2000).
- Johnson, A., Pergamon, Oxford, pp. 171-178 (1985).
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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
“A more recent study in 2009 by Kim et al. (2009) reported maximum clavulanic acid production of 700mg/mL in media supplemented with palm oil, an intermediate value as compared to other oil sources.”
Background
- Authors
- KIM, S.-J., KIM, J.-O., SHIN, C.-H., PARK, H. W., & KIM, C.-W.
- Affiliations
- Korea University (KR)
- Chong Kun Dang Bio (South Korea) (KR)
- Venue
- Bioscience, Biotechnology, and Biochemistry
- Publisher
- Informa UK Limited
- Published
- 2009-01-23
- Volume
- 73
- Issue
- 1
- Pages
- 160-164
- ISSN
- 0916-8451 (ISSN-L)
- 1347-6947
- OpenAlex
- W1974341459
- Cited by
- 15
- References
- 0
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 3 · 2019: 4 · 2018: 1 · 2017: 1 · 2016: 1
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Bioscience Biotechnology and Biochemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Microbial Metabolism and Applications
- Keywords
- clavulanic acid, Streptomyces clavuligerus, oleic acid, triolein, fatty acid hydrolysis, mutant screening, minimum inhibitory concentration, strain improvement, antibiotic production, cell growth
- MeSH terms
- Fatty Acids, Nonesterified, Fermentation, Mutation, Streptomyces, Triolein, Oleic Acid, Clavulanic Acid
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