Screening of Variables Influencing the Clavulanic Acid Production by Streptomyces DAUFPE 3060 Strain

Viana, Daniela; Carneiro-Cunha, M. N.; Araújo, Janete Magalí de; Barros-Neto, Benício; Lima-Filho, José Luiz de; Converti, Attílio; Pessoa, Adalberto; Porto, Ana Lúcia Figueiredo

doi:10.1007/s12010-009-8671-3

Cited by 16 publications

(16 citation statements)

References 26 publications

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“…The experimental design was composed of seven runs, including three repetitions of the central point (Table ) needed to calculate the pure error . Consistently with the results of conventional fermentation in shake flasks, maximum CA production was obtained after 48 h of extractive fermentation in the central point runs; thus, this time was selected as a reference for both responses. A linear regression model was employed to predict each response ( Y ):

Y = b_{0} + \sum b_{i} x_{i} + \sum b_{j} x_{j} + \sum b_{ij} x_{i} x_{j}

where b 0 is the intercept coefficient, b i and b j are the linear coefficients, b ij is the interaction coefficient and x i and x j are the coded values of the independent variables, namely the aeration rate ( x 1 ) and the agitation rate ( x 2 ).…”

Section: Methodssupporting

confidence: 54%

“…The experimental design was composed of seven runs, including three repetitions of the central point (Table 1) needed to calculate the pure error. 28 Consistently with the results of conventional fermentation in shake flasks, 29,30 maximum CA production was obtained after 48 h of extractive fermentation in the central point runs; thus, this time was selected as a reference for both responses. A linear regression model was employed to predict each response (Y):…”

Section: Experimental Designmentioning

confidence: 80%

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Effect of aeration and agitation on extractive fermentation of clavulanic acid by using aqueous two‐phase system

Marques

Santos-Ebinuma

Pessoa

et al. 2016

Biotechnology Progress

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In this work, the effects of agitation and aeration rates on aqueous two-phase system (ATPS)-based extractive fermentation of clavulanic acid (CA) by Streptomyces variabilis DAUFPE 3060 were investigated through a 2 full factorial design, where oxygen transfer rate (OTR) and oxygen uptake rate (OUR) were selected as the responses. Aeration rates significantly influenced cell growth, OUR, and CA yield, while OTR was practically the same in all the runs. Under the intermediate agitation (950 rpm) and aeration conditions (3.5 vvm) of the central point runs, it was achieved OTR of 1.617 ± 0.049 mmol L h , OUR of 0.132 ± 0.030 mmol L h , maximum CA production of 434 ± 4 mg L , oxygen mass transfer coefficient of 33.40 ± 2.01 s , partition coefficient of 66.5 ± 1.5, CA yield in the top and bottom phases of 75% ± 2% and 19% ± 1%, respectively, mass balance of 95% ± 4% and purification factor of 3.8 ± 0.1. These results not only confirmed the paramount role of O supply, broth composition and operational conditions in CA ATPS-extractive fermentation, but also demonstrated the possibility of effectively using this technology as a cheap tool to simultaneously produce and recover CA. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:1444-1452, 2016.

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Y = b_{0} + \sum b_{i} x_{i} + \sum b_{j} x_{j} + \sum b_{ij} x_{i} x_{j}

Section: Methodssupporting

confidence: 54%

Section: Experimental Designmentioning

confidence: 80%

Effect of aeration and agitation on extractive fermentation of clavulanic acid by using aqueous two‐phase system

Marques

Santos-Ebinuma

Pessoa

et al. 2016

Biotechnology Progress

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“…The concentration of CA, taken as dependent variable, was evaluated after 96 h, because previous experiments demonstrated that CA degradation begins after this time 19. The quadratic model to predict the optimal point was expressed by the equation: where b ii are the quadratic coefficients.…”

Section: Experimental Designsmentioning

confidence: 99%

Extractive fermentation of clavulanic acid by Streptomyces DAUFPE 3060 using aqueous two‐phase system

Marques

Pessoa

Lima-Filho

et al. 2010

Biotechnology Progress

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The influence of four variables, specifically PEG molar mass (400, 1,000, and 8,000 g/mol), concentrations of PEG and phosphate salts (15, 20, and 25% for both), and agitation intensity (110, 150, and 200 rpm), on clavulanic acid (CA) extraction by extractive fermentation with PEG/phosphate salts aqueous two-phase system was investigated in shaken flasks using a 2(4-1) -fractional factorial design. After selection of the two most significant variables (agitation intensity and PEG molar mass), an optimization study conducted according to a 2(2) -central composite design revealed that 25% PEG 8,000 g/mol and phosphate salts at 240 rpm (run 6) were the best conditions for the extractive fermentation, leading to the best results in terms of partition coefficient (k = 8.2), yield of CA in the PEG-rich phase (η(T) = 93%) and productivity (P = 5.3 mg/Lh). As a first attempt to make a scale-up of these results, the effectiveness of the extractive fermentation was then checked in a bench-scale bioreactor under conditions as close as possible to the optimum ones determined in flasks. The highest CA concentration obtained in the PEG-rich phase (691 mg/L) was 30% higher than in flasks, thus demonstrating the potential of such a new process, integrating the production and extraction steps, as a promising, low-cost tool to obtain high yields of this and similar products.

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“…CA is a potent antibiotic inhibitor of "serine" (or classes A, C, and D) ␤-lactamases. It is used in conjunction with amoxicillin in a salt (potassium clavulanate) form and prescribed clinically as co-amoxiclav (Augmentin TM in USA, Clavulin TM in Brazil) or with ticarcillin (Timentin TM ) [4].…”

Section: Introductionmentioning

confidence: 99%

Stability of clavulanic acid in PEG/citrate and liquid–liquid extraction in aqueous two-phase system

Carneiro-da-Cunha

Souza

Mota

et al. 2014

Fluid Phase Equilibria

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␤-Lactamases are enzymes responsible for the hydrolysis of ␤-lactam antibiotics, being produced by several pathogenic bacteria. Clavulanic acid is a commercially and clinically important ␤-lactamase inhibitor, its extraction being possible by the application of aqueous two-phase system. In this study, clavulanic acid stability was investigated at different molar mass PEG (400, 1 000 and 20 000 g mol −1) and at different citrate concentrations (5 and 20%) PEG/citrate aqueous-two phase systems (ATPS), under different pH values (4.0-8.0). Clavulanic acid extraction was also evaluated. Low citrate concentration and PEG 20 000 (g mol −1) ATPS, at pH 6.0, were shown to be the systems that presented the highest clavulanic acid stability. Based on this, a factorial design 2 2 was used to evaluate CA extraction, being PEG (20, 25 and 30%) and citrate (5, 10 and 15%) concentrations the parameters evaluated. Clavulanic acid was extracted into the PEG-rich phase (133.66 mg L −1), the highest values of the partition coefficient and yield being K = 5.92, Y = 103.53%, respectively The ATPS was not only effective on clavulanic acid extraction, but also its degradation was minimal. These results clearly indicate that ATPS can be successfully applied as a first step for the purification of clavulanic acid.

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Screening of Variables Influencing the Clavulanic Acid Production by Streptomyces DAUFPE 3060 Strain

Cited by 16 publications

References 26 publications

Effect of aeration and agitation on extractive fermentation of clavulanic acid by using aqueous two‐phase system

Effect of aeration and agitation on extractive fermentation of clavulanic acid by using aqueous two‐phase system

Extractive fermentation of clavulanic acid by Streptomyces DAUFPE 3060 using aqueous two‐phase system

Stability of clavulanic acid in PEG/citrate and liquid–liquid extraction in aqueous two-phase system

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