CoChat
Sign Up
Cited by 90Microbial Natural Products and BiosynthesisEnzyme Production and CharacterizationMicrobial Metabolism and Applications

Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review

Open access
Ser, Hooi-Leng, Law, Jodi Woan-Fei, Chaiyakunapruk, Nathorn, Jacob, Sabrina Anne, Palanisamy, Uma Devi, Chan, Kok-Gan, Goh, Bey-Hing, Lee, Learn-Han·2016·Frontiers in Microbiology
DOI 10.3389/fmicb.2016.00522PMC PMC4840625
Open this paper in CoChat — free accountOpen PDF

Abstract

The β-lactamase inhibitor, clavulanic acid is frequently used in combination with β-lactam antibiotics to treat a wide spectrum of infectious diseases. Clavulanic acid prevents drug resistance by pathogens against these β-lactam antibiotics by preventing the degradation of the β-lactam ring, thus ensuring eradication of these harmful microorganisms from the host. This systematic review provides an overview on the fermentation conditions that affect the production of clavulanic acid in the firstly described producer, Streptomyces clavuligerus. A thorough search was conducted using predefined terms in several electronic databases (PubMed, Medline, ScienceDirect, EBSCO), from database inception to June 30th 2015. Studies must involve wild-type Streptomyces clavuligerus, and full texts needed to be available. A total of 29 eligible articles were identified. Based on the literature, several factors were identified that could affect the production of clavulanic acid in S. clavuligerus. The addition of glycerol or other vegetable oils (e.g., olive oil, corn oil) could potentially affect clavulanic acid production. Furthermore, some amino acids such as arginine and ornithine, could serve as potential precursors to increase clavulanic acid yield. The comparison of different fermentation systems revealed that fed-batch fermentation yields higher amounts of clavulanic acid as compared to batch fermentation, probably due to the maintenance of substrates and constant monitoring of certain entities (such as pH, oxygen availability, etc.). Overall, these findings provide vital knowledge and insight that could assist media optimization and fermentation design for clavulanic acid production in S. clavuligerus.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review of 29 eligible articles reports that fermentation conditions—carbon and nitrogen supplements, pH, temperature, aeration/agitation, and batch versus fed-batch mode—affect clavulanic acid production by wild-type *Streptomyces clavuligerus*. Fed-batch fermentation generally yields more clavulanic acid than batch, while glycerol, vegetable oils, arginine/ornithine, and lower fermentation temperature are highlighted as influential factors.

Key findings

  • Glycerol and vegetable oils can strongly affect clavulanic acid yield. In batch fermentation, olive oil gave 1120 mg/L versus 564 mg/L with glycerol (Salem-Berkhit et al., 2010); Kim et al. (2009) reported triolein at 989 mg/L, olive oil at 820 mg/L, palm oil at 700 mg/L, and corn oil at 380 mg/L. Bellão et al. (2013) found glycerol at 348.5 mg/L versus starch at 125.2 mg/L in batch, and 982.1 mg/L versus 469.0 mg/L in fed-batch.
  • Amino acid effects were inconsistent. Romero et al. (1986) reported 16 μg/mg dry weight with arginine and 9 μg/mg dry weight with ornithine; Chen et al. (2003) found ornithine at 200 mg/L versus arginine at 100 mg/L in batch; Saudagar and Singhal (2007b) reported L-threonine at 1863 mg/L and arginine at 1310 mg/L in fed-batch.
  • Fed-batch fermentation generally produced more clavulanic acid than batch. Examples include 982.1 mg/L versus 348.5 mg/L (Bellão et al., 2013), 1390 mg/L versus 509 mg/L (Teodoro et al., 2010), and 404 mg/L versus 194 mg/L (Neto et al., 2005).
  • Other factors matter: phosphate repressed production (2 mM phosphate gave 90 mg/L versus 3 mg/L at 75 mM; Lebrihi et al., 1987), pH around 7 was optimal, and lower temperature increased yield (20°C gave 1266.2 mg/L versus 631.6 mg/L at 25°C and 168.7 mg/L at 30°C; Costa and Badino, 2012). Redox-cycling agents mostly increased production, with phenazine methosulfate giving 63.73–103.56 mg/L, while methyl viologen gave 9.96–25.89 mg/L (Kwon and Kim, 1998).

Methods

  • PRISMA-guided systematic review; searches in PubMed, Medline, ScienceDirect, and EBSCO from database inception to June 30, 2015, using MeSH terms “Streptomyces,” “clavuligerus” combined with “clavulanic acid” or “clavulanate.”
  • Inclusion required wild-type *S. clavuligerus*, batch and/or fed-batch fermentation conditions, and reporting of specific clavulanic acid amounts; exclusions included mutants, organisms other than *S. clavuligerus*, solid phase extraction, immobilization, reviews, conference abstracts, meta-analyses, comments, and letters. Two reviewers independently screened and extracted data.
  • From 627 records plus 11 additional articles, 474 remained after duplicate removal, 42 full texts were reviewed, and 29 studies were eligible. Extracted data included fermentation type/volume, oxygen/airflow control, media composition and pH, supplements, and maximum clavulanic acid produced; synthesis was qualitative.

Limitations

  • The paper states that measurement inconsistencies and missing standard deviations in some replicated studies prevented quantitative synthesis and meta-analysis.
  • The paper notes that most selected studies used one-factor-at-a-time batch fermentation, limiting multifactorial conclusions, and that results for sugars/glycerol and amino acids were inconsistent.
  • Evident from the text: the search ended June 30, 2015; only wild-type *S. clavuligerus* and specific-production studies were included, excluding mutants and other production systems, so findings may not generalize to industrial strains or newer fermentation strategies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fmicb.2016.00522

Cites

84 of 85 references verified1 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

20 of 120 cited sources checked · 7 supported · 2 flagged · accuracy not yet measured

  • Findingcitation

    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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Kim et al. (2009) source

      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 measured
  • Findingcitation

    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).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Saudagar and Singhal, 2007a source
    • cites Bellão et al., 2013 source
  • Findingcitation

    The 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).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bellão et al., 2013 source

      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 measured
  • Findingcitation

    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.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bellão et al. (2013) source

      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 measured
  • Findingcitation

    Comparing 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).”
    Quote in the paperSubstantial claim2 of 3 sources checked
    • cites Chen et al., 2002 source
    • cites Neto et al., 2005 source
    • cites Bellão et al., 2013 source

      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 measured
  • Classified as probably not a substantial claim. 33
  • May combine two claims. 47

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Researchers would expect a higher yield of end-products from fed-batch fermentation because it entails a scale-up process.

    “Given that the fed-batch fermentation system entails a scale-up process, researchers would expect a higher yield of end-products (Modak et al., 1986; Thiry and Cingolani, 2002; Hewitt and Nienow, 2007).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Modak et al., 1986 source
    • cites Thiry and Cingolani, 2002 source
    • cites Hewitt and Nienow, 2007 source

      The Introduction says that biomass yield and growth-associated products often decrease when aerobic fermentation is scaled up. Although ‘Operational Constraints at the large-scale’ describes fed-batch cultivation as a way to increase volumetric productivity, it does not attribute that increase to scale-up; the claimed reason for expecting a higher yield is contrary to the paper's account. (LLM, conf=0.91)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Clavulanic acid was first purified as a β-lactamase inhibitor from S. clavuligerus ATCC 27064, isolated from South American soil in 1971.

    “Clavulanic acid was first purified as a novel β-lactamase inhibitor from S. clavuligerus ATCC 27064, which was isolated from South American soil in 1971 (Higgens and Kastner, 1971; Brown et al., 1976).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Higgens and Kastner, 1971 source
    • cites Brown et al., 1976 source

      The main text (page unavailable) identifies clavulanic acid as a β-lactamase inhibitor produced by Streptomyces clavuligerus ATCC 27064 and says it was isolated as a sodium salt. It does not say that the strain came from South American soil or was isolated in 1971; those details cannot be verified from this paper. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    This systematic review was carried out in accordance with PRISMA guidelines.

    “This systematic review was carried out in accordance with the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines (Moher et al., 2009).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Moher et al., 2009 source

  • May combine two claims.

    Premisecitation

    Two important precursors for clavulanic acid are arginine (C5 precursor) and glutaraldehyde-3-phosphate (C3 precursor).

    “These efforts then resulted in the identification of two important precursors for clavulanic acid—arginine (C5 precursor) and glutaraldehyde-3-phosphate (C3 precursor) (Romero et al., 1986; Kanehisa and Goto, 2000; Kanehisa et al., 2016).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Romero et al., 1986 source
    • cites Kanehisa and Goto, 2000

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites Kanehisa et al., 2016 source

      The Overview of KEGG describes databases of chemical compounds and reactions, and the antimicrobial-resistance section mentions antibiotic-biosynthesis pathway maps, but neither identifies clavulanic acid precursors. Searches for clavulanic acid, arginine, and the claimed C3 and C5 precursors found no passage addressing the claim. (LLM, conf=0.76)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Interpretationcitation

    High speed stirring prevents cell clumping and causes cell shearing.

    “It is believed that the high speed stirring prevents cell clumping and also causes cell shearing (Toma et al., 1991; Rosa et al., 2005).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Toma et al., 1991 source

      The Conclusions (page unavailable) attribute the effects of excessive stirring to turbulence-induced shear stress, possibly damaging cell membranes; Experimental Results say the microorganisms were stressed, probably by shear effects, without being killed. Neither section addresses whether stirring prevents cell clumping, so the source supports only the shear-related part of the claim. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites Rosa et al., 2005 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clavulanic acid as a β-lactamase inhibitor was initially isolated from S. clavuligerus ATCC 27064 using the traditional fermentation system.

    “Clavulanic acid as a β-lactamase inhibitor was initially isolated from S. clavuligerus ATCC 27064 using the traditional fermentation system (Higgens and Kastner, 1971; Brown et al., 1976).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Higgens and Kastner, 1971 source
    • cites Brown et al., 1976 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Sometimes a large-scale fed-batch fermentation may not generate similar results as observed in small-scale batch fermentation, because the fed-batch fermentation system involves a more dynamic environment.

    “However, it has been suggested that sometimes a large-scale fed-batch fermentation may not generate similar results as observed in small-scale batch fermentation, as the fed-batch fermentation system involves a more dynamic environment (Hewitt and Nienow, 2007).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Hewitt and Nienow, 2007 source

      The Conclusions and Future Perspective section says large-scale fed-batch bioreactors have dynamic spatial and temporal heterogeneities that can reduce biomass and product yields relative to well-mixed laboratory reactors. However, the Experimental Results section compares large-scale fed-batch fermentation with small-scale fed-batch fermentation, not the small-scale batch fermentation specified in the claim. Page numbers are not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Researchers have identified numerous genes involved in clavulanic acid biosynthesis in S. clavuligerus, including the clavaminate synthases genes.

    “With the advancement of next generation sequencing technologies, researchers have identified numerous genes involved in clavulanic acid biosynthesis in S. clavuligerus including the clavaminate synthases genes (Medema et al., 2011).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Medema et al., 2011 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingown data

    The literature search yielded 627 articles, with 11 additional articles from other sources; after duplicate removal 474 articles were accessed, 432 were excluded, 42 full texts were reviewed, and 29 studies were eligible for qualitative analysis.

    “The search yielded a total of 627 articles, while an additional 11 articles were obtained from other sources (Figure 2). After the removal of duplicate records, a total of 474 articles were accessed, out of which 432 articles were excluded based on their titles and abstracts. 42 full text articles were reviewed, out of which 29 studies were eligible for the qualitative analysis according to the in”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    In Lee and Ho (1996), no clavulanic acid production was observed in glycerol-containing media, but higher production occurred in sucrose media (3.63 mg/L).

    “When comparing between glycerol and sucrose as a sole carbon source, Lee and Ho (1996) observed no production of clavulanic acid in media added with glycerol, but higher production of the compound in media with sucrose (3.63 mg/L).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lee and Ho (1996) source

  • Classified as probably not a substantial claim.

    Findingown data

    A total of 29 eligible articles were identified.

    “A total of 29 eligible articles were identified.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Using fermentation media with different pH produced different levels of clavulanic acid, with maximum concentrations reported at pH 7.

    “By using fermentation media with different pH, different levels of clavulanic acid were seen; with maximum concentrations reported at pH 7.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    The optimum KH2PO4 concentration for clavulanic acid production was determined to be 10 mM, with maximum clavulanic acid concentration recorded at 878 mg/L.

    “Thus the optimum concentration of KH2PO4 for clavulanic acid production was determined to be 10 mM (with a maximum clavulanic acid concentration recorded at 878 mg/L).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Romero et al. (1986) reported maximum clavulanic acid concentrations of 16 μg/dry weight biomass with arginine and 9 μg/dry weight biomass with ornithine.

    “Romero et al. (1986) reported maximum concentrations of clavulanic acid in a slightly different manner, where 16 μg/dry weight of biomass was observed with arginine; while 9 μg/dry weight of biomass was observed with ornithine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Romero et al. (1986) source

  • May combine two claims.

    Findingown data

    Among the selected studies, there were seven fed-batch fermentation experiments, with the majority looking at the effect of adding glycerol into the fermenter over time.

    “Among the selected studies, there were a total of seven fed-batch fermentation experiments, with the majority looking at the effect of adding glycerol into the fermenter over a period of time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    The highest maximum clavulanic acid concentration was described with phenazine methosulfate (63.73-103.56 mg/L), followed by plumbagin (55.76-79.66 mg/L), and H2O2 (51.78-69.71 mg/L).

    “The highest maximum clavulanic acid concentration was described with phenazine methosulfate (63.73–103.56 mg/L), followed by plumbagin (55.76–79.66 mg/L), and H2O2 (51.78–69.71 mg/L).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Low fermentation temperature (20°C) resulted in maximum clavulanic acid concentration of 1266.2 mg/L, compared to 631.6 mg/L at 25°C and 168.7 mg/L at 30°C.

    “Low fermentation temperature (20°C) resulted in maximum clavulanic acid concentration as high as 1266.2 mg/L as compared to 631.6 mg/L at 25°C and 168.7 mg/L at 30°C.”
    • Also stated in: § Discussion · boosted
      “Costa and Badino (2012) demonstrated a maximum clavulanic acid concentration of 1266.2 mg/L when fermentation was performed at 20°C.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Costa and Badino (2012) source

  • May combine two claims.

    Findingnone given

    Relatively high clavulanic acid production was observed in media supplemented with corn oil (911 mg/L), followed by cotton seed oil (740 mg/L), and linseed oil (700 mg/L).

    “Relatively high production was also observed in media supplemented with corn oil (911 mg/L), followed by cotton seed oil (740 mg/L), and linseed oil (700 mg/L).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    Cerri and Badino (2012) supported the view that an increase in agitation speed leads to higher clavulanic acid production, but not oxygen flow.

    “A study by Cerri and Badino (2012) also supported the view that an increase in agitation speed leads to higher production of clavulanic acid, but not oxygen flow.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cerri and Badino (2012) source

  • May combine two claims.

    Findingcitation

    Saudagar and Singhal (2007b) showed that using fed-batch fermentation technologies, production of clavulanic acid could be further increased following batch fermentation that revealed increased production by arginine and threonine.

    “Following batch fermentation that revealed increased clavulanic acid production by arginine and threonine, Saudagar and Singhal (2007b) showed that by using fed-batch fermentation technologies; the production of the compound could be further increased.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Saudagar and Singhal (2007b) source

  • May combine two claims.

    Findingcitation

    Chen et al. (2003) reported that fed-batch fermentation using glycerol, ornithine, and arginine yielded different amounts of clavulanic acid, with the highest amount with glycerol (300 mg/L), followed by arginine (210 mg/L), and the lowest with ornithine (110 mg/L).

    “Chen et al. (2003) reported that fed-batch fermentation using glycerol, ornithine, and arginine; yielded different amounts of clavulanic acid, whereby the highest amount was demonstrated with glycerol (300 mg/L), followed by arginine (210 mg/L), and the lowest with ornithine (110 mg/L).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al. (2003) source

  • May combine two claims.

    Findingcitation

    Salem-Berkhit et al. (2010) found that addition of olive oil improved clavulanic acid production compared to glycerol, with maximum concentrations of 1120 and 564 mg/L respectively.

    “These results were consistent with another recent study, whereby the addition of olive oil improved clavulanic acid production as compared to glycerol; with a maximum concentration at 1120 and 564 mg/L, respectively (Salem-Berkhit et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Salem-Berkhit et al., 2010 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingcitation

    Costa and Badino (2012) reported that fermentation temperature may lead to variation in clavulanic acid production.

    “In addition, Costa and Badino (2012) reported that the temperature at which fermentation was carried out may lead to variation in clavulanic acid production.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Costa and Badino (2012) source

  • May combine two claims.

    Findingnone given

    When oxygen flow was increased to 4.1 vvm, maximum clavulanic acid concentration was 269 mg/L, approximately half of the maximum observed with 3 vvm (454 mg/L).

    “When the oxygen flow was increased to 4.1 vvm, the maximum concentration of clavulanic acid was observed to be 269 mg/L, which is approximately half of the maximum concentration observed with an oxygen flow of 3 vvm (454 mg/L).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Among amino acids tested by Saudagar and Singhal (2007b), the highest clavulanic acid concentration was observed with L-threonine, which was not reported in other literature included in the review.

    “Among these amino acids, the highest concentration of clavulanic acid was observed in media supplemented with L-threonine; which was not reported in other literature included in this systematic review.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Saudagar and Singhal (2007b) source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Findingcitation

    Lynch and Yang (2004) suggested that L-lysine is one of the most important amino acids for clavulanic acid production, given that fermentation broths with low L-lysine (1 g/L) failed to yield any clavulanic acid.

    “The study suggested that L-lysine is one of the most important amino acids for the production of clavulanic acid, given that fermentation broths with low concentrations of L-lysine (1 g/L) failed to yield any clavulanic acid.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lynch and Yang (2004) source

  • May combine two claims.

    Findingnone given

    At 800 rpm, two flasks with different oxygen flow rates showed similar maximum clavulanic acid concentrations, with 475 mg/L and 482 mg/L.

    “At 800 rpm, two flasks with different oxygen flow rates showed similar levels of maximum clavulanic acid concentration, with 475 mg/L obtained from the flask with the lowoxygen flow rate and 482 mg/L from the flask with the low oxygen flow rate.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingcitation

    Addition of glycerol together with either amino acid resulted in intermediate values, with glycerol plus arginine producing 130 mg/L and glycerol plus ornithine producing 200 mg/L.

    “The addition of glycerol together with either of the amino acids resulted in intermediate values, where the combination of glycerol and arginine produced 130 mg/L; while glycerol and ornithine resulted in 200 mg/L.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    Based on literature obtained in the study, glycerol was the most popular choice of carbon source in clavulanic acid production, in order to ensure an efficient supply of glyceraldehyde-3-phosphate.

    “Based on literature obtained in this study, glycerol was found to be the most popular choice of carbon source in clavulanic acid production; in order to ensure an efficient supply of glyceraldehyde-3-phosphate”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Arginine and glyceraldehyde-3-phosphate are the two precursors involved in clavulanic acid biosynthesis and undergo a series of enzymatic processes to form the β-lactam inhibitor.

  • May combine two claims.

    Findingcitation

    Even though a low temperature of 20°C was not favorable for the growth of S. clavuligerus, high production yield of clavulanic acid was observed.

    “Even though a low temperature of 20°C was not favorable for the growth of S. clavuligerus, high production yield of clavulanic acid was observed.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Costa and Badino (2012) source

  • May combine two claims.

    Findingcitation

    Rosa et al. (2005) showed that high speed stirring promoted clavulanic acid production, which was associated with a lower amount of biomass production.

    “Rosa et al. (2005) showed that the high speed stirring promoted the production of clavulanic acid, which was associated with a lower amount of biomass production.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Rosa et al. (2005) source

  • Classified as probably not a substantial claim. May combine two claims.

    Findingnone given

    Current studies have reported inconsistent results on the utilization of various sugars (e.g., dextrin and sucrose) and glycerol as sole carbon sources in clavulanic acid production, and the role of these compounds in the biosynthesis pathways is yet to be clearly defined.

    “as current studies have reported inconsistent results and the role of these compounds in the biosynthesis pathways is yet to be clearly defined.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    A total of 29 studies was selected after a thorough literature search in this systematic review.

    “In this systematic review, a total of 29 studies was selected after a thorough literature search.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Clavulanic acid prevents degradation of the β-lactam ring, thereby preventing resistance of pathogens to β-lactam antibiotics.

    “Clavulanic acid prevents drug resistance by pathogens against these β-lactam antibiotics by preventing the degradation of the β-lactam ring, thus ensuring eradication of these harmful microorganisms from the host.”
    • Also stated in: § Introduction · plain
      “Thus, to overcome this resistance, β-lactamase inhibitors are often used in conjunction with β-lactam antibiotics as these compounds prevent the degradation of these antibiotics and increase the efficacy of these drugs (Saudagar et al., 2008).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Saudagar et al., 2008 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Bacteria can resist β-lactam antibiotics by producing β-lactamase, which cleaves the β-lactam ring.

    “One of the strategies deployed by this group of bacteria to survive against β-lactam antibiotics is by the production of a β-lactam-hydrolyzing enzyme – β-lactamase; which functions to neutralize these antibiotics by cleaving the β-lactam ring (Wilke et al., 2005; Toussaint and Gallagher, 2015).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wilke et al., 2005 source
    • cites Toussaint and Gallagher, 2015 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The bibliographies of relevant studies were checked for additional publications.

    “The bibliographies of relevant studies were checked for additional publications.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Clavulanic acid is commercially used with amoxicillin (Augmentin) and is listed as an important antibacterial in the WHO list of essential medicines (2015).

    “Clavulanic acid or clavulanate, is commercially used along with amoxicillin (Augmentin) and this combination has been listed as an important antibacterial agents in the WHO list of essential medicines (2015) (Toussaint and Gallagher, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Toussaint and Gallagher, 2015 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    β-lactam antibiotics act by inhibiting bacterial cell wall synthesis.

    “The β-lactam antibiotics are one of the most popular classes of antibacterial agents, whose mechanism of action is via inhibition of bacterial cell wall synthesis (Page, 2012).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Page, 2012 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Clavulanic acid is used in combination with β-lactam antibiotics to treat a wide spectrum of infectious diseases.

    “The β-lactamase inhibitor, clavulanic acid is frequently used in combination with β-lactam antibiotics to treat a wide spectrum of infectious diseases.”
    • Also stated in: § Introduction · plain
      “Clavulanic acid or clavulanate, is commercially used along with amoxicillin (Augmentin) and this combination has been listed as an important antibacterial agents in the WHO list of essential medicines (2015) (Toussaint and Gallagher, 2015).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Toussaint and Gallagher, 2015 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Any disagreements between the two reviewers were resolved by consensus.

    “Any disagreements between the two reviewers were resolved by consensus.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The search included studies from database inception to June 30th, 2015.

    “We included studies from database inception to June 30th, 2015.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Systematic searches were performed in PubMed, Medline, ScienceDirect, and EBSCO.

    “Systematic searches were performed in the following databases: PubMed, Medline, ScienceDirect, and EBSCO.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Two reviewers independently screened and evaluated all titles and abstracts based on inclusion and exclusion criteria.

    “Two reviewers (H-LS and JW-FL) independently screened and evaluated all titles and abstracts retrieved from the comprehensive search, based on the inclusion and exclusion criteria.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Any discrepancies were discussed between both authors.

    “Any discrepancies were discussed between both authors.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Once glycerol is metabolized into glyceraldehyde-3-phosphate, it can either enter the clavulanic acid biosynthesis pathway or be involved in glycolytic or gluconeogenesis reactions.

    “Once glycerol is metabolized into glyceraldehyde-3-phosphate, it can either enter the clavulanic acid biosynthesis pathway, or be involved in glycolytic or gluconeogenesis reactions (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The pH of the medium could affect the growth of S. clavuligerus, as it is described to grow between pH 5.0 and 8.5, but sporulation is not observed from pH 7.0 to 8.5.

    “Similarly, pH of the medium could affect the growth of S. clavuligerus, as it is described to grow between pH 5.0 and 8.5, however sporulation is not observed from pH 7.0 to 8.5 (Higgens and Kastner, 1971).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Higgens and Kastner, 1971 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Fed-batch fermentation systems represent a high throughput platform as compared to traditional batch fermentation methods.

    “Following media optimization, several studies have also incorporated another strategy to maximize the production of clavulanic acid—by utilizing fed-batch fermentation systems which represent a high throughput platform as compared to traditional batch fermentation methods.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Longobardi, 1994 source
    • cites Li et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    In designing a fermentation media for clavulanic acid production, it is important to ensure that the media can support the proper growth of S. clavuligerus and provide factors that could stimulate the production of valuable secondary metabolites.

    “Thus in designing a fermentation media for clavulanic acid production, it is important to ensure that the media can support the proper growth of S. clavuligerus; as well as provide factors that could stimulate the production of valuable secondary metabolites.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Supplementation of L-threonine prevents anaplerotic flux on pyruvate to synthesize amino acids such as isoleucine, which increases availability of C3 precursors and eventually enhances clavulanic acid production.

    “Indeed the supplementation of L-threonine was found to prevent the anaplerotic flux on pyruvate to synthesize amino acids such as isoleucine, which in turn increased the availability of C3 precursors and eventually enhanced clavulanic acid production (Ives and Bushell, 1997; Bushell et al., 2006; Saudagar and Singhal, 2007b).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ives and Bushell, 1997 source
    • cites Bushell et al., 2006 source
    • cites Saudagar and Singhal, 2007b source

  • May combine two claims.

    Interpretationcitation

    Addition of arginine or ornithine in fermentation media would increase the flow of C5 precursors into the biosynthesis pathway, which would subsequently increase clavulanic acid production.

    “Thus, the addition of arginine or ornithine in fermentation media would increase the flow of C5 precursors into the biosynthesis pathway, which then subsequently increase the production of clavulanic acid (Romero et al., 1986; Lynch and Yang, 2004).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Romero et al., 1986 source
    • cites Lynch and Yang, 2004 source
    • The authors state this as an assumption: S. clavuligerus produces a higher amount of clavulanic acid when there is an adequate supply of the precursors arginine and glyceraldehyde-3-phosphate.

  • May combine two claims.

    Premisecitation

    The availability of oxygen determines the growth and survival of the bacteria as well as production of secondary metabolites, including antibiotics in S. clavuligerus.

    “The availability of oxygen determines the growth and survival of the bacteria as well as production of secondary metabolites, which includes antibiotics in S. clavuligerus (Yegneswaran et al., 1991).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Yegneswaran et al., 1991 source

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    As a scale-up production process, the fed-batch fermentation system often allows an increase in productivity with a concomitant decrease in production cost.

    “As a scale-up production process, the fed-batch fermentation system often allows an increase in productivity with a concomitant decrease in production cost.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    The pH of the media and fermentation temperature may play important roles in clavulanic acid production because these factors could lead to degradation of clavulanic acid.

    “Taken altogether, the pH of the media and fermentation temperature may play important roles in clavulanic acid production as these factors could eventually lead to degradation of this valuable compound.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Wang et al. (2005) proposed using statistical methods to optimize the fermentation media for clavulanic acid production by S. clavuligerus.

    “For instance, Wang et al. (2005) proposed using statistical methods to optimize the fermentation media for clavulanic acid production by S. clavuligerus.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al. (2005) source

  • May combine two claims.

    Premisecitation

    The presence of reactive oxygen species in fermentation media leads to an imbalance in redox status, which could trigger stress and damage microbials, or even lead to cell death.

    “The presence of reactive oxygen species in the fermentation media leads to an imbalance in redox status, which could trigger stress and damage microbials, or even lead to cell death (Cabiscol et al., 2010).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cabiscol et al., 2010

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Saudagar and Singhal (2007a) suggested optimum concentrations of soybean flour (8.8%), soybean oil (1.2%), dextrin (1.0%), yeast extract (1.5%), and KH2PO4 (0.2%), with an optimal pH of 7.0 ± 0.2.

    “By using the L25 orthogonal array method, the study suggested optimum concentrations of soybean flour (8.8%), soybean oil (1.2%), dextrin (1.0%), yeast extract (1.5%), and KH2PO4 (0.2%); with an optimal pH of 7.0 ± 0.2.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Saudagar and Singhal (2007a) source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The main difference between batch and fed-batch fermentation systems is that the latter is frequently monitored with sophisticated technologies and allows precise control of the entire fermentation process.

    “The main difference between batch and fed-batch fermentation systems is that the latter is frequently monitored with the assistance of sophisticated technologies and allows precise control of the entire fermentation process (Longobardi, 1994; Li et al., 2014).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Longobardi, 1994 source
    • cites Li et al., 2014

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationreasoning

    Vegetable oils such as olive oil and corn oil may serve as cost-effective options because they are readily available at a lower cost compared to carbohydrate substrates.

    “Vegetable oils such as olive oil and corn oil may serve as cost-effective options as they are readily available at a lower cost compared to carbohydrate substrates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Temperature and pH control are crucial for the production of clavulanic acid and stability of the compound.

    “In addition, temperature and pH control are also crucial for the production of clavulanic acid and stability of the compound.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Wang et al. (2005) suggested optimal concentrations of soy meal powder (38.102 g/L), FeSO4.7H2O (0.395 g/L), and ornithine (1.177 g/L) for clavulanic acid production.

    “By combining factional factorial design and response surface methodology, the study suggested optimal concentration of three of the most important components identified via factional factorial design—soy meal powder (38.102 g/L), FeSO4.7H2O (0.395 g/L), and ornithine (1.177 g/L).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wang et al. (2005) source

  • May combine two claims.

    Premisecitation

    Compared to glycerol, vegetable oils seem to be a more attractive source of energy, as a typical oil contains about 2.4 times more energy than glycerol.

    “As compared to glycerol, vegetable oils seem to be a more attractive source of energy; as a typical oil contains about 2.4 times more energy than glycerol (Stowell, 1987).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Stowell, 1987

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    S. clavuligerus ATCC 27064 was reported to have optimal growth from 26 to 30°C with no growth above 37°C.

    “S. clavuligerus ATCC 27064 was reported to have optimal growth from 26 to 30°C with no growth above 37°C (Higgens and Kastner, 1971), while most of the selected studies reported that fermentation temperature ranged between 20 and 30°C.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Higgens and Kastner, 1971 source

  • May combine two claims.

    Premisecitation

    The wild type strain of S. clavuligerus is unable to metabolize glucose and lacks expression of the glucose permease gene.

    “The wild type strain of S. clavuligerus is unable to metabolize glucose, and further molecular studies revealed that the strain lacks the expression of the glucose permease gene (Garcia-Dominguez et al., 1989; Pérez-Redondo et al., 2010).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Garcia-Dominguez et al., 1989 source
    • cites Pérez-Redondo et al., 2010 source

  • May combine two claims.

    Premisecitation

    Inclusion of glycerol enhances clavulanic acid production compared to carbohydrates, as glycerol provides a higher energy content on a weight-by-weight basis.

    “The inclusion of glycerol enhances the production of clavulanic acid as compared to carbohydrates, as glycerol provides a higher energy content on a weight-by weight basis (Efthimiou et al., 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Efthimiou et al., 2008 source

  • May combine two claims.

    Premisecitation

    Chen et al. (2003) discovered that arginine increased the production of clavulanic acid in fed-batch but not batch fermentation.

    “Chen et al. (2003) discovered that ornithine increased the production of clavulanic acid in batch but not fed-batch fermentation, while arginine increased the production in fed-batch but not batch fermentation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al. (2003) source

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    The development of scale-up production tools such as fed-batch fermentation systems could offer a budget-friendly method for clavulanic acid production, which is important for the pharmaceutical industry where production cost is a major concern.

    “For the most part, the development of scale-up production tools such as fed-batch fermentation systems could offer a “budget-friendly” method for clavulanic acid production, as this is particularly important for the pharmaceutical industry where production cost is one of the major concerns.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Chen et al. (2003) discovered that ornithine increased the production of clavulanic acid in batch but not fed-batch fermentation.

    “Chen et al. (2003) discovered that ornithine increased the production of clavulanic acid in batch but not fed-batch fermentation, while arginine increased the production in fed-batch but not batch fermentation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chen et al. (2003) source

  • May combine two claims.

    Interpretationreasoning

    The utilization of different oil sources as a sole carbon source and amino acids as a source of nitrogen in the fermentation media seems to have a strong influence on clavulanic acid production in S. clavuligerus, followed by other factors such as pH and temperature.

    “Nevertheless, the utilization of different oil sources as a sole carbon source and amino acids as a source of nitrogen in the fermentation media seems to have a strong influence on clavulanic acid production in S. clavuligerus; followed by other factors such as pH and temperature.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The selected studies are representative of the effects of fermentation conditions on clavulanic acid production in S. clavuligerus.
68 of 68

  • The paper relies on this without support.

    The higher clavulanic acid yields reported for fed-batch compared with batch fermentation are attributable to the fermentation mode rather than to differences in media, strain, scale, or other study conditions.

    “yields higher amounts of clavulanic acid as compared to batch fermentation, probably due to the maintenance of substrates and constant monitoring of certain entities (such as pH, oxygen availability, etc.).”

  • The paper relies on this without support.

    The effects of glycerol or vegetable oils on clavulanic acid production observed across the included studies are attributable to the supplements themselves rather than to other differences among studies.

    “The addition of glycerol or other vegetable oils (e.g., olive oil, corn oil) could potentially affect clavulanic acid production.”

  • The paper relies on this without support.

    The literature search and inclusion criteria captured all relevant studies on fermentation conditions affecting clavulanic acid production in S. clavuligerus.

    “A thorough search was conducted using predefined terms in several electronic databases (PubMed, Medline, ScienceDirect, EBSCO), from database inception to June 30th 2015.”

  • The authors state this as an assumption.

    S. clavuligerus produces a higher amount of clavulanic acid when there is an adequate supply of the precursors arginine and glyceraldehyde-3-phosphate.

    “It is also presumed that S. clavuligerus produces higher amount of clavulanic acid when there is adequate supply of these precursors.”

  • The paper relies on this without support.

    Arginine and glyceraldehyde-3-phosphate are the two precursors involved in clavulanic acid biosynthesis and undergo a series of enzymatic processes to form the β-lactam inhibitor.

    “The two precursors involved in clavulanic acid biosynthesis, arginine and glyceraldehyde-3-phosphate; undergo a series of enzymatic processes to form the β-lactam inhibitor.”

  • The paper relies on this without support.

    The selected studies are representative of the effects of fermentation conditions on clavulanic acid production in S. clavuligerus.

    “Nevertheless, fed-batch fermentation appears to be a better fermentation strategy for clavulanic acid production as demonstrated in the selected studies.”
6 of 6

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • A 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 [5]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Palm-oil concentration is reported in mg/mL instead of mg/L

    Major

    The narrative reports 700 mg/mL for Kim et al. (2009), while Table 1 reports 700 mg/L for the same palm-oil result. The narrative unit makes the concentration 1,000 times the tabulated value.

    Reported 700 · recomputed 700000

  • Precursor has two conflicting chemical names

    Minor

    The introduction names the C3 precursor glutaraldehyde-3-phosphate, whereas the discussion names it glyceraldehyde-3-phosphate. These are not the same name for the stated precursor.

  • Soybean-flour comparison is attributed to the wrong study

    Minor

    The text attributes the 698 versus 338 mg/L comparison to Gouveia et al. (2001), but Table 1 assigns those two results to Ortiz et al. (2007).

3 of 3

Cites

Flagged first, then by citations

4 of the 89 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Stowell, 1987, The application of oils and fats in antibiotic processes, 139
  2. WHO, 2015, WHO Model List of Essential Medicines: 19th list (updated) April 2015

Cited by

Sorted by citations

Related

Authors
Ser, H.-L., Law, J. W.-F., Chaiyakunapruk, N., Jacob, S. A., Palanisamy, U. D., Chan, K.-G., Goh, B.-H., & Lee, L.-H.
Affiliations
  • Monash University Malaysia (MY)
  • University of Malaya (MY)
Corresponding author
  • Goh, Bey-Hing
  • Lee, Learn-Han
ORCID
Venue
Frontiers in Microbiology
Publisher
Frontiers Media SA
Published
2016-04-22
Volume
7
Pages
522-522
ISSN
1664-302X (ISSN-L)
DOI
10.3389/fmicb.2016.00522
PMC
PMC4840625
OpenAlex
W2338595164
Semantic Scholar
c192383bb266b2816894131f51be2b3d81893d67
Cited by
90
References
89
Citations by year
2026: 4 · 2025: 5 · 2024: 5 · 2023: 4 · 2022: 7 · 2021: 14 · 2020: 15 · 2019: 18 · 2018: 9 · 2017: 6 · 2016: 2
FWCI
1.99
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Frontiers in Microbiology (publishedVersion, cc-by)
  • Monash University Research Portal (Monash University) (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Strathprints: The University of Strathclyde institutional repository (University of Strathclyde) (acceptedVersion)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by)
  • PubMed Central (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Kementerian Sains, Teknologi dan Inovasi (GBA-808813, 06-02-10-SF0300, GBA-808138, 02-02-10-SF0215)
  • Universiti Malaya (H‐50001‐A000027, GBA-808813, GBA-808138, A000001-50001, 02-02-10-SF0215)
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, Streptomyces clavuligerus, fermentation conditions, beta-lactamase inhibitors, glycerol supplementation, L-arginine, ornithine, fed-batch fermentation, batch fermentation, fermentation medium optimization, antibiotic resistance

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-13.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-13.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review