Overproduction of clavulanic acid by extractive fermentation

Costa, Cecília Ladeira Lopes; Badino, Alberto Colli

doi:10.1016/j.ejbt.2015.03.001

Cited by 13 publications

(7 citation statements)

References 35 publications

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“…This production has been the subject of intensive research in recent years because of its clinical and commercial importance [ 61 ]. According to Costa and Badino [ 67 ] and Ünsaldı et al [ 65 ], CA fermentation processes provide low CA concentrations, which hinders its large-scale chemical synthesis. Moreover, the commercial CA feasibility is restricted because of its elaborate production process [ 68 ].…”

Section: Producers Of β-Lactamases Inhibitorsmentioning

confidence: 99%

“…Soybean derivatives (flour, protein isolate, and meal) have been used as nitrogen sources for CA production [ 7 , 67 , 70 , 94 , 95 , 97 , 106 , 107 ]. To perform a screening of medium constituents for fermentative CA production by S. clavuligerus , Rodrigues et al [ 70 ] performed fermentations using soybean protein isolate (SPI) and soybean flour (SF) as the primary nitrogen source, and obtained higher CA concentration (437 mg/L) with the former ingredient.…”

Section: Production Of β-Lactamase Inhibitorsmentioning

confidence: 99%

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Production of β-Lactamase Inhibitors by Streptomyces Species

et al. 2018

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β-Lactamase inhibitors have emerged as an effective alternative to reduce the effects of resistance against β-lactam antibiotics. The Streptomyces genus is known for being an exceptional natural source of antimicrobials and β-lactamase inhibitors such as clavulanic acid, which is largely applied in clinical practice. To protect against the increasing prevalence of multidrug-resistant bacterial strains, new antibiotics and β-lactamase inhibitors need to be discovered and developed. This review will cover an update about the main β-lactamase inhibitors producers belonging to the Streptomyces genus; advanced methods, such as genetic and metabolic engineering, to enhance inhibitor production compared with wild-type strains; and fermentation and purification processes. Moreover, clinical practice and commercial issues are discussed. The commitment of companies and governments to develop innovative strategies and methods to improve the access to new, efficient, and potentially cost-effective microbial products to combat the antimicrobial resistance is also highlighted.

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Section: Producers Of β-Lactamases Inhibitorsmentioning

confidence: 99%

Section: Production Of β-Lactamase Inhibitorsmentioning

confidence: 99%

Production of β-Lactamase Inhibitors by Streptomyces Species

et al. 2018

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“… 9 Soybean derivatives (flour, protein isolate, and meal) have been used as sources of nitrogen. 10 , 11 Compounds containing phosphorus and magnesium are also included in culture media used for CA production. 12 Ortiz et al 13 investigated the effects of soybean flour and soybean protein isolate as primary sources of nitrogen on CA production by S. clavuligerus .…”

Section: Introductionmentioning

confidence: 99%

Screening of medium constituents for clavulanic acid production by Streptomyces clavuligerus

Rodrigues

Souza

Badino

et al. 2018

Brazilian Journal of Microbiology

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Clavulanic acid is a β-lactam compound with potent inhibitory activity against β-lactamases. Studies have shown that certain amino acids play essential roles in CA biosynthesis. However, quantitative evaluations of the effects of these amino acids are still needed in order to improve CA production. Here, we report a study of the nutritional requirements of Streptomyces clavuligerus for CA production. Firstly, the influence of the primary nitrogen source and the salts composition was investigated. Subsequently, soybean protein isolate was supplemented with arginine (0.0–3.20 g L−1), threonine (0.0–1.44 g L−1), ornithine (0.0–4.08 g L−1), and glutamate (0.0–8.16 g L−1), according to a two-level central composite rotatable design. A medium containing ferrous sulfate yielded CA production of 437 mg L−1, while a formulation without this salt produced only 41 mg L−1 of CA. This substantial difference suggested that Fe2+ is important for CA biosynthesis. The experimental design showed that glutamate and ornithine negatively influenced CA production while arginine and threonine had no influence. The soybean protein isolate provided sufficient C5 precursor for CA biosynthesis, so that supplementation was unnecessary. Screening of medium components, together with experimental design tools, could be a valuable way of enhancing CA titers and reducing the process costs.

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“…Even though a cost comparison of conventional technique to obtain CA and ATPS‐based extractive fermentation is difficult owing to the use of several recovery steps in the former, it is intuitive that the occurrence of a single production/purification step in the latter is expected to ensure significant cost savings . Furthermore, extractive fermentation can decrease the toxic effects of products generated during microbial growth and, in the specific case of CA, can even improve its production, since CA is well known to act as inhibitor of its own synthesis …”

Section: Introductionmentioning

confidence: 99%

“…18 Furthermore, extractive fermentation can decrease the toxic effects of products generated during microbial growth and, in the specific case of CA, can even improve its production, since CA is well known to act as inhibitor of its own synthesis. 19 As is well known, O 2 availability is fundamental for the growth and metabolism of all aerobic microorganisms. The rate of oxygen uptake by cells in fact depends on several factors like O 2 solubilization, diffusion rate, transfer from the gas to the liquid phase, amount of dissolved O 2 , and bioreactor features.…”

Section: Introductionmentioning

confidence: 99%

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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Overproduction of clavulanic acid by extractive fermentation

Cited by 13 publications

References 35 publications

Production of β-Lactamase Inhibitors by Streptomyces Species

Production of β-Lactamase Inhibitors by Streptomyces Species

Screening of medium constituents for clavulanic acid production by Streptomyces clavuligerus

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

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