Kinetics of rapamycin production by Streptomyces hygroscopicus MTCC 4003
Open accessAbstract
Research work was carried out to describe the kinetics of cell growth, substrate consumption and product formation in batch fermentation of rapamycin using shake flask as well as laboratory-scale fermentor. Fructose was used as the sole carbon source in the fermentation media. Optimization of fermentation parameters and reliable mathematical models were used for the maximum production of rapamycin from Streptomyces hygroscopicus MTCC 4003. The experimental data for microbial production of rapamycin fitted well with the proposed mathematical models. Kinetic parameters were evaluated using best fit unstructured models, viz. Andrew’s model, Monod model, Yano model, Aiba model. Andrew’s model showed a comparatively better R 2 value (0.9849) among all tested models. The values of maximum specific growth rate ( μ max ), saturation constant ( K S ), inhibition constant ( K i ), and growth yield coefficient ( Y X/S ) were found to be 0.008 (h −1 ), 2.835 (g/L), 0.0738 (g/L), and 0.1708 (g g −1) , respectively. The optimum production of rapamycin was obtained at 300 rpm agitation and 1 vvm aeration rate in the fermentor. The final production of rapamycin in shake flask was 539 mg/L. Rapamycin titer found in bioreactor was 1,316 mg/L which is 52 % higher than the latest maximum value reported in the literature.
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Written from the paper’s full text.
TL;DR
This study describes batch rapamycin production by *Streptomyces hygroscopicus* MTCC 4003 with fructose as the sole carbon source and fits unstructured growth models to the data. Andrew’s substrate-inhibition model fit best (R² = 0.9849), and a 2.2-L bioreactor run reached 1,316 mg/L rapamycin, reported as 52% higher than the prior maximum cited.
Key findings
- Fructose gave the highest rapamycin titer among glucose, fructose, mannose, and fructose + mannose; shake-flask production reached 539 mg/L.
- Andrew’s model fit best (R² = 0.9849) with μmax = 0.0083 h⁻¹, KS = 2.835 g/L, and Ki = 0.073 g/L; Monod gave a lower R² = 0.8713 with μmax = 0.003869 h⁻¹ and KS = 0.8271 g/L. The abstract reports μmax = 0.008 h⁻¹, KS = 2.835 g/L, Ki = 0.0738 g/L, and YX/S = 0.1708 g g⁻¹; the results text reports average YX/S = 0.107 g g⁻¹, ranging from 0.0598 to 0.1708.
- In the bioreactor at 300 rpm and 1 vvm, rapamycin reached 1,316.02 mg/L at 144 h, with maximum productivity of 9.13 mg/L h⁻¹; this was 52% higher than the previously reported 860.6 mg/L (Zou and Li 2013). By the 12th day, rapamycin decreased to 91.67 mg/L.
- Rapamycin production started after 24 h and peaked at 144 h; dissolved oxygen was maintained at 10% saturation during fermentation.
Methods
- Batch fermentations used *S. hygroscopicus* MTCC 4003 in 250-mL shake flasks (50 mL medium, 25 °C, 120 rpm, 7 days) and in a 2.2-L stirred tank reactor (2-L working volume, 25 °C, 300 rpm, 1 vvm, pH 7.24, 7 days), with fructose as the sole supplemented carbon source in further studies.
- Biomass was measured as dry weight; residual fructose was measured by DNS; rapamycin was assayed by paper-disc agar diffusion against *Candida albicans* MTCC 227 and by HPLC (C18 column, methanol:acetonitrile 80:20, 272 nm). All experiments were performed in triplicate.
- Growth kinetics were fitted to Monod, Andrew, Yano, and Aiba models using GraphPad Prism 5; YX/S was calculated from experimental data.
Limitations
- Stated: substrate utilization analysis assumed supplemented carbohydrates were the sole carbon and energy source, neglecting carbohydrates present in other medium constituents such as malt extract.
- Stated: because no product inhibition for rapamycin production was reported, only substrate inhibition was considered in modeling.
- Evident: the kinetic and production conclusions come from one strain and lab-scale batch shake-flask/2.2-L bioreactor experiments; no fed-batch or larger-scale validation is reported.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
3 of 16 cited sources checked · 0 supported · 1 flagged · accuracy not yet measured
- Interpretationown data
The bioreactor rapamycin titer is 52% higher than the latest maximum value reported in the literature.
“which is 52 % higher than the latest maximum value reported in the literature.”
- Also stated in: § Results and discussion · plain
“It is 52 % higher than that reported previously (860.6 mg/L) by Zou and Li (2013).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites Zou and Li 2013 source
Table 5 (shown under Conclusion; page unavailable) lists 860.6 mg/l for this study and 783 mg/l as the highest titer among the earlier studies it compares. That is about 10% higher, not 52%. The Results section reports a different comparison: 182% higher than this study’s control. (LLM, conf=0.91)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measured
- Also stated in: § Results and discussion · plain
- Interpretationcitation
Formation of two adjacent peaks in the HPLC chromatogram on the 12th day might be attributed to degradation of rapamycin and consequent production of rapamycin degradation products.
“formation of two adjacent peaks in the HPLC chromatogram might be attributed to degradation of rapamycin and consequent production of rapamycin degradation products (Prapagdee et al. 2008; Wang et al. 1994).”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites Prapagdee et al. 2008 source
The Results and Discussion passage on metabolite stability describes unknown thermostable antifungal compounds, not rapamycin degradation. Searches of our untruncated copy for rapamycin, HPLC chromatograms, adjacent peaks, and day 12 found no passage addressing the proposed explanation. (LLM, conf=0.76)
Experimental — accuracy not yet measured - cites Wang et al. 1994 source
- Interpretationcitation
The decrease in rapamycin concentration on the 12th day might be attributed to rapamycin degrading after 7 days of fermentation.
“This phenomenon was observed by Xu et al. (2005) and might be attributed to the fact that rapamycin starts degrading after 7 days of fermentation (Prapagdee et al. 2008).”
Quote in the paperSubstantial claim1 of 2 sources checked- cites Xu et al. 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites Prapagdee et al. 2008 source
The Results and Discussion section reports that antifungal activity decreased as fungal incubation continued, but it does not identify the metabolite as rapamycin or discuss its degradation. Searches for rapamycin degradation after seven days and concentration on day 12 found no supporting passage in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measured
- Findingown data
The experimental data for microbial production of rapamycin fitted well with the proposed mathematical models.
“The experimental data for microbial production of rapamycin fitted well with the proposed mathematical models.”
Quote in the paperSubstantial claim - Findingown data
The maximum specific growth rate (μmax) was found to be 0.008 h−1.
“The values of maximum specific growth rate (μmax), saturation constant (KS), inhibition constant (Ki), and growth yield coefficient (YX/S) were found to be 0.008 (h−1), 2.835 (g/L), 0.0738 (g/L), and 0.1708 (g g−1), respectively.”
Quote in the paperNot a substantial claim
- Findingown data
Andrew's model showed a comparatively better R2 value (0.9849) among all tested models.
“Andrew’s model showed a comparatively better R2 value (0.9849) among all tested models.”
- Also stated in: § Results and discussion · boosted
“Andrew’s model for substrate inhibition on microbial growth was found to fit the experimental values well, since an R2 value of 0.9849 was obtained (Fig. 2a).”
Quote in the paperSubstantial claim - Also stated in: § Results and discussion · boosted
- Findingown data
YX/S values ranged from 0.0598 to 0.1708.
“Its values ranged from 0.0598 to 0.1708 and were found to be maximal at lower S and minimal at higher S because of the substrate inhibition on YX/S.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Substrate used for product formation and cell maintenance is negligible.
- The authors state this as an assumption: Fructose is consumed for cell growth and cell maintenance.
- Findingown data
The Monod model maximum specific growth rate (μmax) was 0.003869 h−1.
“The growth kinetic parameters, viz. μmax and KS were found to be 0.003869 h−1 and 0.8271 g/L.”
Quote in the paperSubstantial claim - Findingown data
The Andrew's model inhibition constant (Ki) was 0.073 g/L.
“The values of μmax, KS and Ki were found to be 0.0083 h−1, 2.835 and 0.073 g/L, respectively.”
Quote in the paperSubstantial claim - Findingown data
The Andrew's model maximum specific growth rate (μmax) was 0.0083 h−1.
“The values of μmax, KS and Ki were found to be 0.0083 h−1, 2.835 and 0.073 g/L, respectively.”
Quote in the paperSubstantial claim - Findingown data
The inhibition constant (Ki) was found to be 0.0738 g/L.
“The values of maximum specific growth rate (μmax), saturation constant (KS), inhibition constant (Ki), and growth yield coefficient (YX/S) were found to be 0.008 (h−1), 2.835 (g/L), 0.0738 (g/L), and 0.1708 (g g−1), respectively.”
Quote in the paperSubstantial claim - Findingown data
Optimum production of rapamycin was obtained at 300 rpm agitation and 1 vvm aeration rate in the fermentor.
“The optimum production of rapamycin was obtained at 300 rpm agitation and 1 vvm aeration rate in the fermentor.”
Quote in the paperSubstantial claim - Findingnone given
In rapamycin production, the increase in biomass concentration was accompanied by a decrease of fructose concentration.
“In rapamycin production, the increase in biomass concentration was accompanied by a decrease of fructose concentration.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Supplemented carbohydrates are the sole source of carbon and energy, and the amount of carbohydrate present in other media constituents is negligible.
- Findingown data
The saturation constant (KS) was found to be 2.835 g/L.
“The values of maximum specific growth rate (μmax), saturation constant (KS), inhibition constant (Ki), and growth yield coefficient (YX/S) were found to be 0.008 (h−1), 2.835 (g/L), 0.0738 (g/L), and 0.1708 (g g−1), respectively.”
- Also stated in: § Results and discussion · plain
“The values of μmax, KS and Ki were found to be 0.0083 h−1, 2.835 and 0.073 g/L, respectively.”
Quote in the paperSubstantial claim - Also stated in: § Results and discussion · plain
- Findingown data
Streptomyces hygroscopicus MTCC 4003 showed a conventional growth pattern during the batch fermentation in the bioreactor.
“Streptomyces hygroscopicus MTCC 4003 showed a conventional growth pattern during the batch fermentation in the bioreactor (Fig. 3a).”
Quote in the paperNot a substantial claim - Findingown data
Rapamycin titer in bioreactor was 1,316 mg/L.
“Rapamycin titer found in bioreactor was 1,316 mg/L which is 52 % higher than the latest maximum value reported in the literature.”
- Also stated in: § Results and discussion · plain
“From the equation given in the Fig. 3a, the concentration of the 6th day’s sample was calculated to be 1,316.02 mg/L which is the highest rapamycin produced in the bioreactor till date.”
- Also stated in: § Conclusion · plain
“Sixth day sample of fermentation gave the highest rapamycin titer of 1,316 mg/L in bioreactor quantified using HPLC technique.”
Quote in the paperSubstantial claim - Also stated in: § Results and discussion · plain
- Findingown data
Fructose together with nitrogen source casein and (NH4)2SO4 supported good growth and rapamycin production by S. hygroscopicus MTCC 4003.
“However, our result suggested that fructose together with nitrogen source casein and (NH4)2SO4 supported good growth and rapamycin production by the employed strain (Fig. 1).”
Quote in the paperSubstantial claim - Findingcitation
On the 12th day of fermentation, rapamycin concentration decreased significantly to 91.67 mg/L.
“On the 12th day of fermentation, rapamycin concentration decreased significantly to 91.67 mg/L.”
Quote in the paperSubstantial claim - Findingown data
The growth yield coefficient (YX/S) was found to be 0.1708 g g−1.
“The values of maximum specific growth rate (μmax), saturation constant (KS), inhibition constant (Ki), and growth yield coefficient (YX/S) were found to be 0.008 (h−1), 2.835 (g/L), 0.0738 (g/L), and 0.1708 (g g−1), respectively.”
Quote in the paperNot a substantial claim - Findingown data
The Monod model saturation constant (KS) was 0.8271 g/L.
“The growth kinetic parameters, viz. μmax and KS were found to be 0.003869 h−1 and 0.8271 g/L.”
Quote in the paperSubstantial claim - Findingnone given
Extraction of rapamycin with methanol gave higher yield of rapamycin.
“Extraction of rapamycin with methanol gave higher yield of rapamycin.”
Quote in the paperNot a substantial claim - Findingown data
Maximum rapamycin productivity of 9.13 mg/L h−1 was obtained in bioreactor.
“In the present study, maximum rapamycin productivity of 9.13 mg/L h−1 was obtained in bioreactor (Table 2).”
Quote in the paperSubstantial claim - Findingown data
Maximum/final rapamycin production in shake flask was 539 mg/L using fructose as sole carbon source in combination with casein and (NH4)2SO4.
“The final production of rapamycin in shake flask was 539 mg/L.”
- Also stated in: § Conclusion · plain
“The maximum production of rapamycin in the shake flask was found to be 539 mg/L using fructose as sole carbon source in combination with casein and (NH4)2SO4.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- Findingown data
The average YX/S value was 0.107 g g−1.
“The average YX/S value was calculated to be 0.107 g g−1 and was fairly constant up to fructose concentration of 0.548 g/L and then decreased to minimal at fructose concentration of 27 g/L.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Substrate used for product formation and cell maintenance is negligible.
- The authors state this as an assumption: Fructose is consumed for cell growth and cell maintenance.
- Premisecitation
Low titer of rapamycin produced by S. hygroscopicus limits further development and industrialization of this natural product.
“The low titer of this drug produced by the organism has now become a rate-limiting factor in further development and industrialization of this natural product (Zhu et al. 2010).”
- Also stated in: § Conclusion · plain
“Low titers of rapamycin produced by different strains of S. hygroscopicus limits the large-scale industrial production of this potent natural product.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Zhu et al. 2010 source
- Also stated in: § Conclusion · plain
- Premisereasoning
Kinetic studies of growth and rapamycin production by S. hygroscopicus have not been satisfactorily done.
“In the literature, although there are many reports describing optimization of the media (Refaat and Abdel-Fatah 2008) and improvement of strain for better production of rapamycin (Xu et al. 2005; Jung et al. 2011), kinetic studies of growth and rapamycin production by S. hygroscopicus have not been satisfactorily done yet.”
Quote in the paperSubstantial claim0 of 3 sources checked - Premisecitation
Actual growth and rapamycin production kinetic parameters for S. hygroscopicus were not determined.
“Though an attempt was made by Schuhmann and Bergter investigating the branch formation, and cytological properties of mycelial growth of Streptomyces hygroscopicus on solid media (Schuhmann and Bergter 1976), the actual growth and rapamycin production kinetic parameters were not determined.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Schuhmann and Bergter 1976 source
- Study design and conductown data
The calibration curve of rapamycin standard had R2 = 0.9954.
“The calibration curve of rapamycin standard was prepared by plotting HPLC peak area against known rapamycin standard concentrations (R2 = 0.9954) (Fig. 4a).”
Quote in the paperSubstantial claim - Interpretationcitation
The lower R2 value of 0.8713 in Monod's model suggested reasonable substrate or product inhibition on growth of the organism.
“The lower correlation coefficient (R2) value of 0.8713 found in Monod’s model suggested that there was reasonable substrate or product inhibition on growth of the organism (Bhunia et al. 2012).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Bhunia et al. 2012 source
- Rests on an assumption: There is no product inhibition for rapamycin production.
- Study design and conductown data
The HPLC retention time for rapamycin standard was 2.884 min.
“For each concentration of rapamycin standard HPLC retention time (RT) was found to be 2.884 min (Fig. 4b).”
Quote in the paperNot a substantial claim - Interpretationown data
The higher R2 value found with Andrew's model indicates that it is a comparatively better fitted model for the experimental data than Monod and other substrate inhibition models.
“The higher R2 value found with Andrew’s model indicates that it is comparatively better fitted model for the experimental data than Monod and other substrate inhibition models (Table 1).”
Quote in the paperSubstantial claim - Study design and conductown data
The presence of rapamycin in the methanolic extract was confirmed by its retention time (2.814 min), about same as that of rapamycin standard.
“Its presence was confirmed by its retention time (2.814 min) which is about same as that of rapamycin standard (Fig. 4c).”
Quote in the paperSubstantial claim - Interpretationcitation
The obtained data clearly show that exponential phase of growth is very important for rapamycin production.
“However, the obtained data clearly show that exponential phase of growth is very important for rapamycin production (Zhu et al. 2010; Sanchez and Brana 1996).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning
Fructose concentration regulates the microbial growth pattern.
“Analysis of the Monod’s model under different substrate concentration conditions suggested that fructose concentration regulates the microbial growth pattern.”
Quote in the paperSubstantial claim - Interpretationown data
The 6th day sample gave the highest rapamycin titer in bioreactor till date.
“which is the highest rapamycin produced in the bioreactor till date.”
- Also stated in: § Conclusion · plain
“Sixth day sample of fermentation gave the highest rapamycin titer of 1,316 mg/L in bioreactor quantified using HPLC technique.”
Quote in the paperSubstantial claim - Also stated in: § Conclusion · plain
- May combine two claims. 4
- Classified as probably not a substantial claim. 4
May combine two claims.
Findingown dataYX/S was fairly constant up to fructose concentration of 0.548 g/L and then decreased to minimal at fructose concentration of 27 g/L.
“The average YX/S value was calculated to be 0.107 g g−1 and was fairly constant up to fructose concentration of 0.548 g/L and then decreased to minimal at fructose concentration of 27 g/L.”
Quote in the paperNot a substantial claim- The authors state this as an assumption: Substrate used for product formation and cell maintenance is negligible.
- The authors state this as an assumption: Fructose is consumed for cell growth and cell maintenance.
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationRapamycin production increased rapidly during end of the exponential phase and early stationary phase.
“Rapamycin production was observed to increase rapidly during end of the exponential phase and early stationary phase (Xu et al. 2005).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Xu et al. 2005
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
May combine two claims.
Findingown dataAmong the carbohydrates used, fructose yielded the highest rapamycin titer, better than mannose.
“It can be seen in Fig. 1, among the carbohydrates used fructose yielded highest rapamycin titer.”
- Also stated in: § Conclusion · plain
“Fructose was found to be a better carbon source than mannose.”
Quote in the paperSubstantial claim- Also stated in: § Conclusion · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
FindingcitationThe dissolved oxygen level was maintained at 10% of saturation level all the time.
“Finally, the DO level was maintained at 10 % of saturation level all the time (Zhu et al. 2010).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites Zhu et al. 2010 source
May combine two claims.
Findingown dataThe production of rapamycin started after 24 h of incubation and reached a maximal at 144 h.
“The production of rapamycin was started after 24 h of incubation and reached a maximal at 144 h (Fig. 3a).”
Quote in the paperSubstantial claimClassified as probably not a substantial claim.
PremisecitationRapamycin is an antibiotic produced by Streptomyces hygroscopicus.
“Rapamycin, also known as sirolimus, is an antibiotic commonly used as a potent antifungal and immunosuppressant drug produced by the soilborne actinomycete Streptomyces hygroscopicus (Fang and Demain 1995).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites Fang and Demain 1995 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenAll experiments were performed in triplicate.
“All the experiments were performed in triplicate.”
- Also stated in: § Analytical procedures · plain
“All experiments were done in triplicate.”
Quote in the paperNot a substantial claim- Also stated in: § Analytical procedures · plain
May combine two claims.
Interpretationown dataYX/S was maximal at lower S and minimal at higher S because of substrate inhibition on YX/S.
“Its values ranged from 0.0598 to 0.1708 and were found to be maximal at lower S and minimal at higher S because of the substrate inhibition on YX/S.”
Quote in the paperSubstantial claim- The authors state this as an assumption: Substrate used for product formation and cell maintenance is negligible.
- The authors state this as an assumption: Fructose is consumed for cell growth and cell maintenance.
The authors state this as an assumption.
Substrate used for product formation and cell maintenance is negligible.
“However, if the substrate used for product formation and cell maintenance is assumed to be negligible, Eq (4) can be written as:5”
The authors state this as an assumption.
Supplemented carbohydrates are the sole source of carbon and energy, and the amount of carbohydrate present in other media constituents is negligible.
“Hence, analysis of substrate utilization was done by assuming supplemented carbohydrates as sole source of carbon and energy, thereby neglecting the amount of carbohydrate present in other media constituents.”
The authors state this as an assumption.
Fructose is consumed for cell growth and cell maintenance.
“It is assumed that fructose is consumed for cell growth and cell maintenance.”
The paper relies on this without support.
There is no product inhibition for rapamycin production.
“Since, there was no report of product inhibition for rapamycin production, the effect of substrate inhibition was only considered for modeling.”
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.
Sixth-day HPLC chromatogram is assigned to conflicting figures
MinorThe text calls Figure 3c the sixth-day HPLC chromatogram, while the Figure 4 caption assigns that analysis to Figure 4c; Figure 3 is captioned as a time-course profile.
“Figure 3c represents the HPLC chromatogram of methanolic extract of supernatant after 6 days of fermentation.”
“Figure: Fig. 4 a Calibration curve between the HPLC peaks areas and respective concentration of rapamycin standard; b HPLC peak of rapamycin standard; c HPLC analysis of rapamycin produced on 6th day of fermentation; d HPLC analysis of rapamycin on 12th day of fermentation”
Fermentor cultivation duration is given as both seven and eight days
MinorThe methods specify seven days of fermentor cultivation, whereas the results say it was operated for eight consecutive days.
“Compressed sterile air was sparged at 1 vvm cultivating for 7 days at 25 °C.”
“The fermentor was operated with constant impeller speed of 300 rpm for 8 consecutive days.”
Growth yield coefficient is reported as its maximum rather than its average
MinorThe abstract reports YX/S as 0.1708 g g−1, but the results identify 0.1708 as the maximum and give the average as 0.107 g g−1.
“The values of maximum specific growth rate (μmax), saturation constant (KS), inhibition constant (Ki), and growth yield coefficient (YX/S) were found to be 0.008 (h−1), 2.835 (g/L), 0.0738 (g/L), and 0.1708 (g g−1), respectively.”
“The average YX/S value was calculated to be 0.107 g g−1”
Concentration calculation cites the time-course figure instead of the calibration figure
MinorThe paper says the concentration was calculated from an equation in Figure 3a, but identifies Figure 4a as the HPLC calibration curve used to calculate concentrations.
“From the equation given in the Fig. 3a, the concentration of the 6th day’s sample was calculated to be 1,316.02 mg/L”
“The calibration curve of rapamycin standard was prepared by plotting HPLC peak area against known rapamycin standard concentrations (R2 = 0.9954) (Fig. 4a).”
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BackgroundMorélon, E., Mamzer, M., Péraldi, M., et al. (2001) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/16.1.18 · Cited by 65 · cited 2× · see citing works
“…drugs inhibit the first phase of T-cell activation by blocking calcineurin, serine/threonine phosphatase (transcriptional activator of IL-2 gene); whereas, rapamycin interferes with the second phase of T-cell activation by blocking the IL-2 dependent signal transduction (Morelon et al. 2001).”
BackgroundCell density influences antibiotic biosynthesis in Streptomyces clavuligerus
Sánchez, L., & Braña, A. F. (1996) · Microbiology · doi:10.1099/13500872-142-5-1209 · Cited by 64 · cited 1× · see citing works
“However, the obtained data clearly show that exponential phase of growth is very important for rapamycin production (Zhu et al. 2010; Sanchez and Brana 1996).”
BackgroundEffect of nitrogen source on biosynthesis of rapamycin by Streptomyces hygroscopicus
Lee, M. S., Kojima, I., & Demain, A. L. (1997) · Journal of Industrial Microbiology & Biotechnology · doi:10.1038/sj.jim.2900434 · Cited by 61 · cited 3× · see citing works
“, where they showed that a combination of fructose and mannose resulted in good growth of the organisms and consequent higher rapamycin titer (Lee et al. 1997).”
BackgroundResultCarbon source nutrition of rapamycin biosynthesis inStreptomyces hygroscopicus
Kojima, I., Cheng, Y. R., Mohan, V. P., & Demain, A. L. (1995) · Journal of Industrial Microbiology & Biotechnology · doi:10.1007/bf01573954 · Cited by 57 · cited 4× · see citing works
“Bioassay determination of rapamycin was performed by ‘‘paper-disc agar diffusion method’’ as described by Kojima et al. (1995). The assay was conducted in agar plates of assay medium (‘‘Microorganisms’’) seeded with C.”
MethodResultInfluentialXu, Z., Shen, W., Chen, X.-Y., Lin, J., & Cen, P. (2005) · Biotechnology Letters · doi:10.1007/s10529-005-8463-y · Cited by 54 · cited 5× · see citing works
“This phenomenon was observed by Xu et al. (2005) and might be attributed to the fact that rapamycin starts degrading after 7 days of fermentation (Prapagdee et al. 2008).”
BackgroundResultInfluentialNicoletti, F., Lamenta, C., Donati, S., Spada, M., Ranazzi, A., Cacopardo, B. S., Mangano, K., Belardelli, F., Perno, C. F., & Aquaro, S. (2008) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2008.03780.x · Cited by 54 · cited 1× · see citing works
“2010; Graziani 2009), its pharmaceutical activities (Prapagdee et al. 2008; Park et al. 2010; Weber et al. 2005; Foroncewicz et al. 2005; Nicoletti et al. 2009), strain improvement (Zhu et al.”
BackgroundMikroskopische Untersuchungen zur Wachstumskinetik vonStreptomyces hygroscopicus
Schuhmann, E., & Bergter, F. (1976) · Zeitschrift für allgemeine Mikrobiologie · doi:10.1002/jobm.3630160305 · Cited by 53 · cited 1× · see citing works
“Though an attempt was made by Schuhmann and Bergter investigating the branch formation, and cytological properties of mycelial growth of Streptomyces hygroscopicus on solid media (Schuhmann and Bergter 1976), the actual growth and rapamycin production kinetic parameters were not determined.”
BackgroundZhu, X., Zhang, W., Chen, X., Wu, H., Duan, Y., & Xu, Z. (2010) · Biotechnology and Bioengineering · doi:10.1002/bit.22819 · Cited by 48 · see citing works
Mikroskopische Untersuchungen zur Wachstumskinetik von Streptomyces hygroscopicus
Schuhmann, E., & Bergter, F. (1976) · Zeitschrift für allgemeine Mikrobiologie · doi:10.1002/jobm.19760160305 · Cited by 44 · cited 1× · see citing works
“Though an attempt was made by Schuhmann and Bergter investigating the branch formation, and cytological properties of mycelial growth of Streptomyces hygroscopicus on solid media (Schuhmann and Bergter 1976), the actual growth and rapamycin production kinetic parameters were not determined.”
BackgroundWang, C. P., Chan, K. W., Schiksnis, R. A., Scatina, J., & Sisenwine, S. F. (1994) · Journal of Liquid Chromatography · doi:10.1080/10826079408013519 · Cited by 42 · cited 2× · see citing works
“4d that shows the lower rapamycin concentration noted in the 12th day’s sample and formation of two adjacent peaks in the HPLC chromatogram might be attributed to degradation of rapamycin and consequent production of rapamycin degradation products (Prapagdee et al. 2008; Wang et al. 1994).”
BackgroundGeneration of high-yield rapamycin-producing strains through protoplasts-related techniques
Chen, X., Wei, P., Fan, L., Yang, D. J., Zhu, X., Shen, W., Xu, Z., & Cen, P. (2009) · Applied Microbiology and Biotechnology · doi:10.1007/s00253-009-1918-7 · Cited by 41 · cited 2× · see citing works
“…(Prapagdee et al. 2008; Park et al. 2010; Weber et al. 2005; Foroncewicz et al. 2005; Nicoletti et al. 2009), strain improvement (Zhu et al. 2010; Xu et al. 2005; Chen et al. 2009) and optimization of physiological factors for better production of rapamycin (Zou and Li 2013; Chen et al. 2008).”
BackgroundCheng, Y. R., Hauck, L., & Demain, A. L. (1995) · Journal of Industrial Microbiology & Biotechnology · doi:10.1007/bf01569962 · Cited by 36 · cited 2× · see citing works
“Hence, after inoculation, 50 mL of samples were taken from shake flask in 50 mL centrifuge tube at every 24 h interval starting from 0th h and centrifuged at 3,500 rpm for 15 min (Cheng 1995).”
MethodRao, C. S., Madhavendra, S. S., Madhavendra, S. S., et al. (2008) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-008-8147-x · Cited by 35 · see citing works
Efficacy of rapamycin in patient with juvenile rheumatoid arthritis
Foroncewicz, B., Mucha, K., Pączek, L., Chmura, A., & Rowinski, W. A. (2005) · Transplant International · doi:10.1111/j.1432-2277.2004.00070.x · Cited by 34 · cited 4× · see citing works
“2005) and autoimmune diseases such as rheumatoid arthritis (Foroncewicz et al. 2005).”
BackgroundInfluentialKinetic Studies of Alkaline Protease from Bacillus licheniformis NCIM-2042
Bhunia, B. (2012) · Journal of Microbiology and Biotechnology · doi:10.4014/jmb.1206.06015 · Cited by 29 · see citing works
Self-citationRapamycin rescue therapy in patients after kidney transplantation: first clinical experience
WEBER, T. R., Abendroth, D. K., & Schelzig, H. (2005) · Transplant International · doi:10.1111/j.1432-2277.2004.00032.x · Cited by 26 · cited 4× · see citing works
“activity due to inhibition of T-cell activation and proliferation has led to its potential use in clinical treatment of graft rejection in organ transplant (Weber et al. 2005) and autoimmune diseases such as rheumatoid arthritis (Foroncewicz et al.”
BackgroundInfluentialExogenous shikimic acid stimulates rapamycin biosynthesis inStreptomyces hygroscopicus
Fang, A., & Demain, A. L. (1995) · Folia Microbiologica · doi:10.1007/bf02818516 · Cited by 26 · cited 1× · see citing works
“Rapamycin, also known as sirolimus, is an antibiotic commonly used as a potent antifungal and immunosuppressant drug produced by the soilborne actinomycete Streptomyces hygroscopicus (Fang and Demain 1995).”
BackgroundGraziani, E. I. (2009) · ChemInform · doi:10.1002/chin.200934228 · Cited by 17 · see citing works
DCO2 on-line measurement used in rapamycin fed-batch fermentation process
Chen, Y., Krol, J., Huang, W., Cino, J., Vyas, R., Mirro, R., & Vaillancourt, B. (2008) · Process Biochemistry · doi:10.1016/j.procbio.2007.12.013 · Cited by 16 · cited 1× · see citing works
“…(Prapagdee et al. 2008; Park et al. 2010; Weber et al. 2005; Foroncewicz et al. 2005; Nicoletti et al. 2009), strain improvement (Zhu et al. 2010; Xu et al. 2005; Chen et al. 2009) and optimization of physiological factors for better production of rapamycin (Zou and Li 2013; Chen et al. 2008).”
BackgroundZou, X., & Li, J. (2013) · Annals of Microbiology · doi:10.1007/s13213-012-0597-2 · Cited by 13 · cited 5× · see citing works
“It has also been reported to have antitumor, neuroprotective and anti-aging properties (Zou and Li 2013).”
BackgroundInfluentialAbdel-Fattah, Y. R. (2008) · Research Journal of Microbiology · doi:10.3923/jm.2008.405.413 · Cited by 5 · see citing works
Flagged first, then by citations
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Kiki, C., Rashid, A., Wang, Y., Li, Y., Zeng, Q., Yu, C.-P., & Sun, Q. (2019) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2019.121985 · Cited by 246 · see citing works
Biosynthesis of Polyketides in Streptomyces
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Gene Therapy Tools for Brain Diseases
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An overview of rapamycin: from discovery to future perspectives
Yoo, Y. J., Kim, H., Park, S. R., & Yoon, Y. J. (2016) · Journal of Industrial Microbiology & Biotechnology · doi:10.1007/s10295-016-1834-7 · Cited by 114 · see citing works
“2L bioreactor, which is almost the highest rapamycin obtained on batch cultivation in the literature [30].”
BackgroundTian, J., Yang, G., Gu, Y., Sun, X.-Q., Lü, Y., & Jiang, W. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa602 · Cited by 83 · see citing works
Artificial intelligence in healthcare: a mastery
Mukherjee, J., Sharma, R., Dutta, P., & Bhunia, B. (2023) · Biotechnology and Genetic Engineering Reviews · doi:10.1080/02648725.2023.2196476 · Cited by 43 · see citing works
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Self-citationDutta, S., Basak, B., Bhunia, B., Sinha, A., & Dey, A. (2017) · World Journal of Microbiology and Biotechnology · doi:10.1007/s11274-017-2260-3 · Cited by 22 · see citing works
Self-citationRegulation of Secondary Metabolites of Actinobacteria
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Self-citationFormulation of cost-effective medium and optimization studies for enhanced production of rapamycin
Ganesh, S. K., & Devi, C. S. (2023) · Microbial Cell Factories · doi:10.1186/s12934-023-02201-3 · Cited by 9 · see citing works
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The rapamycin sTORy: 50-year journey from Easter Island to the frontiers of biology and medicine
Xiao, X., & Dokudovskaya, S. (2026) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2026.02.004 · Cited by 4 · see citing works
Ganesh, S. K., & Devi, C. S. (2025) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-024-06072-y · Cited by 3 · see citing works
“(Dutta et al., 2014).”
Phaeochromycins I–K, Three Methylene-Bridged Dimeric Polyketides from Streptomyces sp. 166#
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Holistic Approaches for Enhanced Production of Prodigiosin—a Natural Biocolour
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Self-citationBioactive pigment production by marine bacteria from Colombian estuarine and deep–sea environments
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“The highest production rate (6.17 mg/L·h) occurred between 96 and 144 h, when growth was no longer exponential, confirming a non-growth-associated secondary-metabolite pattern consistent with other bioactive compounds in Streptomyces 67 .”
InfluentialDevelopment of Conditions of Submerged Biosynthesis of Landomycin A
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Rapamycin Overproduction by Combined Mutational Study
Dutta, S., & Dey, A. (2019) · Current Biochemical Engineering · doi:10.2174/2212711906666191127095557 · Cited by 1 · see citing works
Self-citationEffects of Glycerol and Shikimic Acid on Rapamycin Production in Streptomyces rapamycinicus
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Current Update on Rapamycin Production and its Potential Clinical Implications
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Розроблення умов глибинного біосинтезу антибіотика ландоміцину А
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Kothalawala, P., & Siriwatwechakul, W. (2022) · ASEAN Engineering Journal · doi:10.11113/aej.v12.17097
“Hence, YX/S is used in assessing the biomass yield based on the limiting substrate utilization in batch growth [31, 32, 33]:”
BackgroundMethodK. Ganesh, S., & C, S. D. (2023) · Figshare · doi:10.6084/m9.figshare.24172260
- Authors
- Dutta, S., Basak, B., Bhunia, B., Chakraborty, S., & Dey, A.
- Affiliations
- National Institute of Technology Durgapur (IN)
- National Institute of Technology Agartala (IN)
- Corresponding author
- Dey, Apurba
- Venue
- 3 Biotech
- Published
- 2013-12-01
- Volume
- 4
- Issue
- 5
- Pages
- 523-531
- ISSN
- 2190-572X (ISSN-L)
- 2190-5738
- PMC
- PMC4162898
- OpenAlex
- W2085344350
- Cited by
- 26
- References
- 36
- Citations by year
- 2026: 2 · 2025: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 6 · 2018: 1 · 2017: 4 · 2016: 1
- FWCI
- 0.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- 3 Biotech (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (submittedVersion, cc-by)
- PubMed Central (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Pharmacology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Physical Sciences › Engineering › Biomedical Engineering › Fluid Dynamics and Mixing
- Keywords
- Streptomyces hygroscopicus, batch fermentation kinetics, unstructured kinetic model, Monod kinetics, fructose carbon source, fermentation parameter optimization, shake flask fermentation, bioreactor scale-up
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