b r a z i l i a n j o u r n a l o f m i c r o b i o l o g y 4 9 (2 0 1 8) 832–839 ht t p: / /www.bjmicrobio l .com.br / Biotechnology and Industrial Microbiology Screening of medium constituents for clavulanic acid production by Streptomyces clavuligerus Kaio César da Silva Rodriguesa, Arianne Tairyne de Souzab, Alberto Colli Badinoa, Danielle Biscaro Pedrolli c, Marcel Otavio Cerri c,∗ a Universidade Federal de São Carlos, Departamento de Engenharia Química, São Carlos, SP, Brazil b Universidade Federal de São João del-Rei, Campus Alto Paraopeba, Departamento de Química, Biotecnologia e Bioprocessos, Ouro Branco, MG, Brazil c Universidade Estadual Paulista (UNESP), Departamento de Bioprocessos e Biotecnologia, Araraquara, SP, Brazil a r t i c l e i n f o Article history: Received 15 August 2017 Accepted 24 January 2018 Available online 15 March 2018 Associate Editor: Adalberto Pessoa Keywords: Clavulanic acid Streptomyces clavuligerus Ferrous sulfate Amino acids supplementation a b s t r a c t Clavulanic acid is a �-lactam compound with potent inhibitory activity against �- 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 require- ments 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 differ- ence suggested that Fe2+ is important for CA biosynthesis. The experimental design showed that glutamate and ornithine negatively influenced CA production while arginine and thre- onine 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. © 2018 Sociedade Brasileira de Microbiologia. Published by Elsevier Editora Ltda. This is s arti an open acces Introduction Clavulanic acid (CA) is a �-lactam compound with potent inhibitory activity against �-lactamases.1 These enzymes cat- alyze the hydrolysis of �-lactam ring in antibiotics, hence ∗ Corresponding author. E-mail: marcel@fcfar.unesp.br (M.O. Cerri). https://doi.org/10.1016/j.bjm.2018.01.006 1517-8382/© 2018 Sociedade Brasileira de Microbiologia. Published by BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) cle under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). inactivating them.2 Although CA is considered an antibi- otic, it has weak antibacterial activity and is ineffective if administrated alone. Therefore, CA in the form of the potas- sium salt is used in conjunction with �-lactamase-sensitive antibiotics such as penicillin and cephalosporin.3 Such com- binations increase the effectiveness of infection treatments, which makes CA clinically and economically important. Elsevier Editora Ltda. This is an open access article under the CC . https://doi.org/10.1016/j.bjm.2018.01.006 http://www.bjmicrobiol.com.br/ http://crossmark.crossref.org/dialog/?doi=10.1016/j.bjm.2018.01.006&domain=pdf http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ mailto:marcel@fcfar.unesp.br https://doi.org/10.1016/j.bjm.2018.01.006 http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ http://creativecommons.org/licenses/by-nc-nd/4.0/ r o b i c a i p d a t h u d s a C b n v e m t b c h m p s C s s e a t i C r t y S a t e m b a i d t c d o b p u c p w m s ornithine, and glutamate significantly affect CA biosynthesis. In this study, these amino acids were chosen as the indepen- dent variables, denoted x1, x2, x3, and x4. The response variable Table 1 – Compositions of inoculum and production media M1–M5. Composition (g L−1) M1 M2 M3 M4 M5 Glycerol 15.0 15.0 15.0 18.0 18.0 Yeast extract 1.0 1.0 1.0 – – Soybean protein isolate 20.0 20.0 20.0 – – Soybean flour – – – 38.0 38.0 Ornithine – – 1.2 1.2 1.2 MOPS 21.0 21.0 21.0 21.0 21.0 K2HPO4 0.8 0.5 0.5 – – KH2PO4 – – – 0.125 0.4 MgSO4·7H2O 0.75 0.4 0.4 0.2 0.5 FeSO ·7H O – 0.4 0.4 0.4 0.4 b r a z i l i a n j o u r n a l o f m i c Traditionally, CA is produced from cultures of Streptomyces lavuligerus, a filamentous aerobic bacterium belonging to the ctinomycetes group.4 Although numerous studies concern- ng CA production have been published in recent decades,5 the rocess can still be improved. Strategies to enhance CA pro- uction include manipulation of bioreactor operation mode6 nd conditions of agitation and aeration,7 as well as optimiza- ion of medium composition.8 Many different culture media ave been reported for CA production. Recent studies have sed glycerol or lipid as carbon and energy sources.9 Soybean erivatives (flour, protein isolate, and meal) have been used as ources of nitrogen.10,11 Compounds containing phosphorus nd magnesium are also included in culture media used for A production.12 Ortiz et al.13 investigated the effects of soy- ean flour and soybean protein isolate as primary sources of itrogen on CA production by S. clavuligerus. Soybean flour pro- ided the highest CA production. Teodoro et al.14 evaluated the ffect of the initial concentration of the nitrogen source in the edium. A high initial nitrogen concentration (about 4.5 g L−1 otal N) resulted in greater release of catabolic products in the roth, inhibiting CA production. Use of an initial total N con- entration of about 3.0 g L−1 provided good cell growth and the ighest CA production among the cultivations tested. Some compounds are directly used to build the CA olecule and are essential for CA biosynthesis. This henomenon has been extensively studied and is well under- tood. The first reaction is the condensation of precursors of 5 and C3 units.15 The C5 precursor is arginine,16 which can be ynthesized from ornithine and glutamate.17 Khaleeli et al.15 howed that the C3 precursor originates from glycerol. Chen t al.18 studied the effects of feeding glycerol, ornithine and rginine on CA production in batch cultures. The combina- ion glycerol and ornithine (molar ratio of 22:1) significantly ncreased CA production and provided greater stimulation of A biosynthesis, compared to glycerol and arginine (molar atio of 22:1). Wang et al.12 examined the effect of the addi- ion of ornithine at different concentrations. The highest CA ield was obtained using 1.2 g L−1 of ornithine. Saudagar and inghal19 evaluated the influence of feeding with glycerol, rginine, and threonine in fed-batch cultures, finding that the wo amino acids acted to stimulate CA production. Domingues t al.20 optimized the glycerol:ornithine molar ratio in the feed edium in continuous cultures using a 5 L working volume ioreactor. The best molar ratio was approximately 40:1. Progress has been made in elucidating the roles of amino cids such as ornithine, arginine, threonine, and glutamate n CA biosynthesis. However, few studies have quantitatively etermined the effects of these amino acids in CA produc- ion. The aim of this study was therefore to screen several ompounds involved in CA biosynthesis, using experimental esign. This is a very useful tool that enables analysis not only f the effects of individual factors, but also the interactions etween factors, in order to find the best conditions for the rocess. Firstly, cultivations were carried out in order to eval- ate the influence of the primary nitrogen source and salts omposition on CA production. Subsequently, the effect on CA roduction of supplementation of the primary nitrogen source ith the amino acids arginine, threonine, ornithine, and gluta- ate was evaluated using experimental design and response urface analysis. o l o g y 4 9 (2 0 1 8) 832–839 833 Materials and methods Microorganism The strain of S. clavuligerus used in this study was purchased from the American Type Culture Collection (ATCC-27064). Veg- etative cells were stored at −70 ◦C in cryotubes with 10% (v v−1) glycerol. Culture media The seed medium had the following composition (g L−1 in dis- tilled water), as proposed by Rosa et al.21: glycerol, 10.0; yeast extract, 1.0; bacto peptone, 10.0; malt extract, 10.0; K2HPO4, 2.5; MgSO4·7H2O, 0.75; MnCl2·4H2O, 0.001; FeSO4·7H2O, 0.001; ZnSO4·7H2O, 0.001; 3-(N-morpholino) propanesulfonic acid (MOPS) buffer, 21.0 (100 mM). The inoculum and production media had the same com- position. First, the influence of the primary nitrogen source (soybean flour – SF and soybean protein isolate – SPI) and the salts composition (FeSO4·7H2O, K2HPO4, KH2PO4, and MgSO4·7H2O) was investigated. Five different production media (M1–M5) were tested, based on those reported previ- ously by Teodoro et al.14 and Wang et al.12 Table 1 presents the media compositions (g L−1 in distilled water). Subsequently, the influence on CA production of supplementation of the primary nitrogen source with the amino acids arginine, thre- onine, ornithine, and glutamate was investigated using an experimental design. The M2 medium containing SPI was used as the basis for supplementation and the amounts of amino acids were altered according to the experimental design. In all cases, the pH of the medium was adjusted to 6.8, followed by autoclaving at 121 ◦C for 15 min. Experimental design A two-level central composite rotatable design (CCRD) and response surface methodology22 were employed in this study. Previous reports12,16,18,19 indicated that arginine, threonine, 4 2 MnCl2·4H2O 0.001 0.001 0.001 – – ZnSO4·7H2O 0.001 0.001 0.001 – – i c r o b i o l o g y 4 9 (2 0 1 8) 832–839 500 400 300 200 100 0 M1 M2 M3 M4 M5 Medium C C A ( M G .L -1 ) 60 h 72 h 84 h 96 h Fig. 1 – Time courses of CA concentration (CCA) for 834 b r a z i l i a n j o u r n a l o f m was the CA concentration. A second order polynomial was used to calculate the predicted response (Eq. (1)). ŷ = b0 + b1x1 + b2x2 + b3x3 + b4x4 + b11x2 1 + b22x2 2 + b33x2 3 + b44x2 4 + b12x1x2 + b13x1x3 + b14x1x4 + b23x2x3 + b24x2x4 + b34x3x4 (1) In Eq. (1), ŷ represents the predicted response; b0 is the intercept; b1, b2, b3, and b4 are the linear terms; b11, b22, b33, and b44 are the quadratic terms; b12, b13, b14, b23, b24, and b34 are the interaction terms; and x1, x2, x3, and x4 are the independent variables studied. A total of 26 experiments were carried out, with 16 facto- rial points, 8 axial points ( ̨ = 2), and 2 central points. Statistica (version 7.0) software was used for the regression and for con- structing the response surface for analysis of the experimental data. Cultivation procedure Vegetative cell suspensions kept in cryotubes (3.5 mL) were inoculated into 50 mL of seed medium in 500 mL Erlen- meyer flasks, followed by incubation in a rotary shaker (New Brunswick Scientific) at 27 ◦C and 250 rpm for 24 h. Erlenmeyer flasks (250 mL) containing 22.5 mL of inoculum medium were inoculated with 2.5 mL of the cultivated seed broth and incu- bated at 27 ◦C and 250 rpm for 24 h. In the production stage, the inoculum suspensions were transferred (using a proportion of 10% v v−1) to 250 mL Erlenmeyer flasks containing 22.5 mL of production medium, followed by incubation at 27 ◦C and 250 rpm for 72–84 h. The M1–M5 cultivations were performed in duplicate, with samples (1 mL) being withdrawn at 48, 60, 72, and 84 h. In the factorial design runs, samples were only removed at 72 h. The samples were centrifuged at 3720 × g for 15 min to obtain a clear supernatant for CA analyses. Determination of clavulanic acid concentration The CA concentration in the fermentation broth was deter- mined spectrophotometrically, as described by Bird et al.23 A volume of 0.4 mL of sample was added to 2.0 mL of imidazole solution (60 g L−1 and pH 6.8). After a 15 min period at 30 ◦C, the derivative produced by the reaction between CA and imidazole was detected at 311 nm. The standard used was CA contained in the pharmaceutical product Clavulin ® (Glaxo-SmithKline Farmacêutica, Rio de Janeiro, Brazil). Results Influence of primary nitrogen source and salts composition Firstly, in order to evaluate the effects of the primary nitrogen source and the salts composition, cultivations were carried out using the five production media (M1–M5). The time courses of CA production (CCA) are shown in Fig. 1. The M1 medium was based on that proposed by Teodoro et al.,14 in which SPI was used as the primary nitrogen source. The M2 and M3 media were similar to M1, but with modification of the salts composition. The M4 medium was the same as the one used by Wang et al.,12 containing SF as the primary nitrogen source, while the M5 medium had an altered salt composition, cultivations with the M1, M2, M3, M4, and M5 media. compared to M4. The total nitrogen concentration was the same in all the media. The highest and lowest maximum CA production (CCAmax) in the broth were obtained after 60 h in M2 (437 mg L−1) and 48 h in M1 (41 mg L−1), respectively. The main difference between the compositions of the media used in these assays was the presence of ferrous sulfate in M2, which indicated the importance of this salt for CA biosynthesis. CCAmax in M2 was 1.34-fold higher than in M3 (325 g L−1), which contained ornithine. With respect to primary nitrogen sources tested, SPI supported higher CA production than SF present in M4 (CCAmax = 317 mg L−1) and M5 media (CCAmax = 196 mg L−1). In contrast, the CA production remained steady for longer in M4 and M5. Quantitative effects of amino acids supplementation Since the highest CCAmax was achieved in the M2 medium, which contained SPI as primary nitrogen source, M2 was chosen as the basis for supplementation with amino acids, according to the experimental design. Table 2 summarizes the two-level four-factor CCRD, with the ranges and levels of the independent variables (arginine, threonine, ornithine, and glutamate) and the corresponding CA concentrations after 72 h of cultivation (response variable). The runs were conducted randomly in order to minimize errors in the exper- imental design. The results shown in Table 2 were used to evaluate the effects of the variables on the CA concentra- tion and obtain the regression coefficients for the second order polynomial model. Statistica software (version 7.0) was employed for these analyses, adopting a 95% confidence level. The Pareto diagram shown in Fig. 2 illustrates the influ- ence of the independent variables on the CA concentration, considering the effects of linear (l) and quadratic (q) terms. The horizontal bars show the magnitudes of the effects and the vertical line (p = 0.05) indicates the limit above which an effect was considered statistically significant. It can be seen that CA production was significantly influenced by glutamate and ornithine. The linear effect of glutamate was most impor- tant in reducing the CA concentration. Although the quadratic term for glutamate showed a positive effect, the negative b r a z i l i a n j o u r n a l o f m i c r o b i o l o g y 4 9 (2 0 1 8) 832–839 835 Table 2 – Ranges and levels of the independent variables, in coded and original units, according to the two-level four-factor CCRD, and results of CA concentration after 72 h of cultivation. Run Independent variables (g L−1) CA concentration (mg L−1) Arginine (x1) Threonine (x2) Ornithine (x3) Glutamate (x4) 1 −1 (0.8) −1 (0.36) −1 (1.02) −1 (2.04) 536.9 2 +1 (2.4) −1 (0.36) −1 (1.02) −1 (2.04) 502.9 3 −1 (0.8) +1 (1.08) −1 (1.02) −1 (2.04) 479.1 4 +1 (2.4) +1 (1.08) −1 (1.02) −1 (2.04) 422.3 5 −1 (0.8) −1 (0.36) +1 (3.06) −1 (2.04) 311.8 6 +1 (2.4) −1 (0.36) +1 (3.06) −1 (2.04) 262.5 7 −1 (0.8) +1 (1.08) +1 (3.06) −1 (2.04) 300.0 8 +1 (2.4) +1 (1.08) +1 (3.06) −1 (2.04) 403.3 9 −1 (0.8) −1 (0.36) −1 (1.02) +1 (6.12) 24.6 10 +1 (2.4) −1 (0.36) −1 (1.02) +1 (6.12) 0.0 11 −1 (0.8) +1 (1.08) −1 (1.02) +1 (6.12) 0.0 12 +1 (2.4) +1 (1.08) −1 (1.02) +1 (6.12) 1.9 13 −1 (0.8) −1 (0.36) +1 (3.06) +1 (6.12) 58.8 14 +1 (2.4) −1 (0.36) +1 (3.06) +1 (6.12) 7.6 15 −1 (0.8) +1 (1.08) +1 (3.06) +1 (6.12) 35.5 16 +1 (2.4) +1 (1.08) +1 (3.06) +1 (6.12) 0.0 17 0 (1.6) 0 (0.72) 0 (2.04) 0 (4.08) 173.9 18 0 (1.6) 0 (0.72) 0 (2.04) 0 (4.08) 175.8 19 −2 (0.0) 0 (0.72) 0 (2.04) 0 (4.08) 234.1 20 +2 (3.2) 0 (0.72) 0 (2.04) 0 (4.08) 100.0 21 0 (1.6) −2 (0.0) 0 (2.04) 0 (4.08) 392.4 22 0 (1.6) +2 (1.44) 0 (2.04) 0 (4.08) 145.5 23 0 (1.6) 0 (0.72) −2 (0.0) 0 (4.08) 14.7 24 0 (1.6) 0 (0.72) +2 (4.08) 0 (4.08) 9.0 25 0 (1.6) 0 (0.72) 0 (2.04) −2 (0.0) 717.1 26 0 (1.6) 0 (0.72) 0 (2.04) +2 (8.16) 1.9 Glu (q) Glu (1) Orn/Glu Orn (q) Orn (1) Thre (1) Thre (1) Arg (1) Thre/Orn Thre/Glu Arg (q) Arg/Glu Arg/Thre Arg/Orn p = 0.05 -0.05 -0.18 -0.30 0.34 0.70 1.07 -1.39 1.70 1.86 -2.01 -2.71 3.03 3.25 -15.13 Fig. 2 – Pareto diagram for CA concentration, at a 95% c e a w r t p c t m a c 600 800 400 200 0 0 200 400 600 800 Observed values of CCA (mg L-1) P re di ct ed v al ue s of C C A ( m g L-1 ) Fig. 3 – Observed versus predicted CA concentrations (mg L−1). Table 3 – Analysis of variance for the regression model of CA production. Source of variation Degrees of freedom Square sum Mean square Fcal Regression 4 1,007,064 251,766 54.70a Residuals 21 96,652 4602 – onfidence level. ffect of the linear term was considerably higher. Ornithine lso had a negative effect on CA production. Statistical evaluation of the significance of the fitted model as performed using analysis of variance (ANOVA), with the esults shown in Table 3. This analysis was carried out using he F-test to determine the quality of the fit and the associated robability p-value. Calculation of the determination coeffi- ient (R2) provided a measure of the extent of variation (using he regression equation). The ANOVA results revealed that the odel was statistically significant (at the 95% confidence level) nd was able to satisfactorily describe the data, since the cal- ulated F value (54.70) was higher than the tabulated value Total 25 1,103,716 – – a F6;47;0.05 = 2.84; R2 = 0.9124. i c r o b i o l o g y 4 9 (2 0 1 8) 832–839 3.06 2.04 1.02 0.00 4.08 8, 16 6, 12 4, 08 2, 04 0, 00 Glutarnate (g L -1) -400 -200 200 400 600 800 0 C C A ( M G .L -1 ) Omith ine (g L -1 ) M1 and M2 media indicated the importance of the fer- rous sulfate for CA biosynthesis, as mentioned by Wang 836 b r a z i l i a n j o u r n a l o f m (2.84). The coefficient of determination (R2 = 0.9124) was also satisfactory, indicating that 91.24% of the variation in the CA concentration could be explained. The observed and predicted CA concentrations are shown in Fig. 3. Eq. (2) shows the second order regression equation with the estimated coefficients. The model was simplified by the elimination of statistically insignificant terms. The indepen- dent variables x3 (ornithine) and x4 (glutamate) are expressed as their coded values and the CA concentration values at 72 h of cultivation are expressed in mg L−1. CCA = 210.90 − 188.37x4 − 47.03x2 3 + 39.88x2 4 + 46.19x3x4 (2) The response surface method consists of the association of the independent and dependent variables of a model in the form of a surface graph. This method was used to identify the best conditions for amino acid supplementation of the primary nitrogen source, maximizing CA production. Fig. 4 shows the response surface for CA concentration as a func- tion of the concentrations of the amino acids ornithine and glutamate. The most evident feature was the decrease in CA yield at higher glutamate concentrations. The model predicted a maximum CA concentration when the glutamate concen- tration was minimal. The distorted contours associated with the axes of ornithine and glutamate suggested interaction between these two parameters. C5 precursor C3 precursor NH2 NH2 HO2C CO2H CO2H CO2H CO2H NH2 NH2 H2N OH OH H H H N N O O CHO O O OHHO O O OOO NH NH L-arginine NH NH NHceasS ceasS gcasS bls 2 1 7 N2-(2-carboxyethyl)-arginine P D-glyceraldehyde-3- phosphate NH N O O O N-glycyl clavaminic acid 8 Clavaminic acid Clavaldehyde Fig. 5 – CA biosynthetic pathway starting from C3 and C5 precur enzymes; the broken line indicates the step for which no enzym synthase; gcaS, glycylclavaminate synthase; bls, �-lactam synth amidinohydrolase; cad, clavaldehyde dehydrogenase. Adapted from Ozcengiz and Demain.26 Fig. 4 – Response surface for CA concentration as a function of the independent variables ornithine and glutamate. Discussion The substantial difference between the CCAmax values in et al.12 The CA biosynthesis employs l-arginine (C5-precursor) and d-glyceraldehyde 3-phosphate (C3-precursor) in nine NH2 NH2 NH2 NH2 CO2H CO2H CO2H CO2H H N O O COOH COOH O O N O O HN NH NH NH cas cascas cad pah 3 4 5 9 5 N N N H H HO HO GuanidinoproclavaminateDeoxyguanidino proclavaminic acid Proclavaminic acid Dihydroclavaminic acid Clavulanic acid sors. Solid lines represent steps catalyzed by known e has yet been characterized. ceaS, carboxyethylarginine etase; cas, clavaminate synthase; pah, proclavaminate b r a z i l i a n j o u r n a l o f m i c r o b i o l o g y 4 9 (2 0 1 8) 832–839 837 Glucose-6-P Gluconeogenesis Fructose-6-P Glyceraldehyde-P Glycolysis 3-P-glycerate PEP Pyruvate Anaplerotic Oxaloacetate TCA cycle 2- oxoglutarate NH3 Glutamate Ammonium released Asparagine Ornithine Urea cycle Arginine succinate Arginine C3 precursor C5 precursor Clavulanic acid Threonine Aspartate NH4 Glycerol Fig. 6 – CA biosynthetic pathway in S. clavuligerus showing the conversion of glutamate to 2-oxoglutarate, which causes the release of ammonium. A c N r S m o 1 i i e C f o C e ( ( d m A fl o m g e t M dapted from Bushell et al.17 atalyzed reactions, as shown in Fig. 5. The conversion of -glycylclavaminic acid to clavaldehyde (step 8) is the only eaction for which the enzyme has not yet been characterized. ix enzymes are known to catalyze the other eight steps. Five onofunctional enzymes catalyze steps 1, 2, 4, 7, and 9, while ne multifunctional enzyme, clavaminate synthase (cas, EC .14.11.21), catalyzes steps 3, 5, and 6. Clavaminate synthase s a nonheme Fe2+-dependent enzyme present as two isoforms n S. clavuligerus.24,25 The iron dependency of this essential nzyme in the CA biosynthesis explains the improvement in A production observed when the medium was enriched with errous sulfate. The lower CCAmax value achieved in M3 (containing rnithine) compared to M2 contrasts with the findings of hen et al.,18 who reported that CA production could be nhanced by adding ornithine to a batch culture. In M4, CCAmax 317 mg L−1) was lower than those reported by Wang et al.12 670 mg L−1) using the same medium. An explanation for this ifference lies in the cultivation procedures used and the edia employed for strain preservation and propagation.27,28 ccording to Mayer and Deckwer,29 the presence of soybean our particles in the medium might induce the production f extracellular proteases by S. clavuligerus. These proteases aintained the degradation of soybean flour during the rowth phase, providing a steady supply of essential nutri- nts to the microorganism. This explains the maintenance of he CA production steady for longer in M4 and M5 relative to 2. With respect to experimental design results, in the biosyn- thetic pathway in S. clavuligerus (Fig. 6), glutamate can be converted to 2-oxoglutarate, which enters the citric acid cycle. The conversion is catalyzed by a glutamate dehydroge- nase and releases ammonium (see Fig. 6), which inhibits CA biosynthesis30 and induces CA degradation,31 hence explain- ing the negative influence of glutamate on CA production. Although the glycerol supply was high, supplementation with C5 precursors (arginine, ornithine, and glutamate) did not result in any increase in CA production. This could be attributed to possible overload of the capacity of carboxyethy- larginine synthase (CeaS2) to process the substrates. In such a scenario, the soybean protein isolate would provide suffi- cient arginine (as a C5 precursor) for the enzyme dosage in the cell, making supplementation unnecessary under the selected production conditions. The commercial soybean protein iso- late used in this study (Nutrisoy Alimentos) contained arginine (8.0% w/w), threonine (3.6% w/w), and glutamate (20.4% w/w), which reinforces this assumption. Conclusion The findings demonstrated that ferrous sulfate should be included in the composition of fermentation media used for CA production, because the enzymes involved in CA biosynthesis are Fe2+-dependent. In contrast, according to the results of the experimental design, supplementation of media i c r o r 838 b r a z i l i a n j o u r n a l o f m containing soybean protein isolate with amino acids (arginine, threonine, ornithine, and glutamate) is unnecessary, since the isolate provides enough C5 precursor (arginine) for CA biosyn- thesis, under the conditions tested. This study simultaneously investigated the influence of several medium constituents in order to determine the best formulation for CA production by S. clavuligerus. This approach is especially important for maximizing CA yields, as well as for reducing the cost of fer- mentative production of CA. Conflicts of interest The authors declare no conflicts of interest. Acknowledgments The authors would like to thank Coordination for the Improve- ment of Higher Education Personnel (CAPES, Brazil) and the National Council for Scientific and Technological Devel- opment (CNPQ, Brazil, Process Number 471848/2013-1) for financial support of this work. e f e r e n c e s 1. Brown AG, Butterworth D, Cole M, Hanscomb G, Hood JD, Reading C. Naturally-occurring beta-lactamase inhibitors with antibacterial activity. J Antibiot. 1976;29(6):668–669. 2. Bush K, Jacoby GA, Medeiros AA. A functional classification scheme for beta-lactamases and its correlation with molecular-structure. Antimicrob Agents Chemother. 1995;39(6):1211–1233. 3. Baggaley KH, Brown AG, Schofield CJ. Chemistry and biosynthesis of clavulanic acid and other clavams. Nat Prod Rep. 1997;14(4):309–333. 4. Higgens C, Kastner R. Streptomyces clavuligerus sp. nov., a �-lactam antibiotic producer. Int J Syst Evol Microbiol. 1971;21(4):326–331. 5. Ser HL, Law JWF, Chaiyakunapruk N, et al. Fermentation conditions that affect clavulanic acid production in Streptomyces clavuligerus: a systematic review. Front Microbiol. 2016;7. 6. Bellão C, Antonio T, Araujo MLGdC, Badino AC. Production of clavulanic acid and cephamycin C by Streptomyces clavuligerus under different fed-batch conditions. Braz J Chem Eng. 2013;30(2):257–266. 7. Marques DAV, Santos-Ebinuma VC, Pessoa A, Porto ALF, Torres BR, Converti A. Effect of aeration and agitation on extractive fermentation of clavulanic acid by using aqueous two-phase system. Biotechnol Prog. 2016;32:1444–1452. 8. Said IG, Abdelwahed NAM, Awad HM, Shallan MA, El-Shahed KYI, Abdel-Rahim EA. Enhancement of clavulanic acid production by Streptomyces sp. MU-NRC77 via mutation and medium optimization. Trop J Pharm Res. 2017;16: 31–42. 9. Vasconcelos EdS, Lima VAd, Goto LS, Cruz-Hernández IL, Hokka CO. Clavulanic acid production by the MMS 150 mutant obtained from wild type Streptomyces clavuligerus ATCC 27064. Braz J Microbiol. 2013;44(4):1049–1057. 10. Marques DAV, Santos-Ebinuma VdC, Sobral de Oliveira PM, et al. Screening of wild type Streptomyces isolates able to overproduce clavulanic acid. Braz J Microbiol. 2014;45(3):919–928. b i o l o g y 4 9 (2 0 1 8) 832–839 11. Costa CLL, Badino AC. Overproduction of clavulanic acid by extractive fermentation. Electron J Biotechnol. 2015;18(3):154–160. 12. Wang YH, Yang B, Ren J, Dong ML, Liang D, Xu AL. Optimization of medium composition for the production of clavulanic acid by Streptomyces clavuligerus. Process Biochem. 2005;40(3–4):1161–1166. 13. Ortiz SCA, Hokka CO, Badino AC. Utilization of soybean derivatives on clavulanic acid production by Streptomyces clavuligerus. Enzyme Microb Technol. 2007;40(5): 1071–1077. 14. Teodoro JC, Baptista-Neto A, Cruz-Hernandez IL, Hokka CO, Badino AC. Influence of feeding conditions on clavulanic acid production in fed-batch cultivation with medium containing glycerol. Appl Microbiol Biotechnol. 2006;72(3):450–455. 15. Khaleeli N, Li RF, Townsend CA. Origin of the beta-lactam carbons in clavulanic acid from an unusual thiamine pyrophosphate-mediated reaction. J Am Chem Soc. 1999;121(39):9223–9224. 16. Valentine BP, Bailey CR, Doherty A, et al. Evidence that arginine is a later metabolic intermediate than ornithine in the biosynthesis of clavulanic acid by Streptomyces clavuligerus. J Chem Soc Chem Commun. 1993:1210–1211. 17. Bushell ME, Kirk S, Zhao HJ, Avignone-Rossa CA. Manipulation of the physiology of clavulanic acid biosynthesis with the aid of metabolic flux analysis. Enzyme Microb Technol. 2006;39(1):149–157. 18. Chen KC, Lin YH, Wu JY, Hwang SCJ. Enhancement of clavulanic acid production in Streptomyces clavuligerus with ornithine feeding. Enzyme Microb Technol. 2003;32(1):152–156. 19. Saudagar PS, Singhal RS. Optimization of nutritional requirements and feeding strategies for clavulanic acid production by Streptomyces clavuligerus. Bioresour Technol. 2007;98(10):2010–2017. 20. Domingues LCG, Teodoro JC, Hokka CO, Badino AC, Araujo MLGC. Optimisation of the glycerol-to-ornithine molar ratio in the feed medium for the continuous production of clavulanic acid by Streptomyces clavuligerus. Biochem Eng J. 2010;53:7–11. 21. Rosa JC, Neto AB, Hokka CO, Badino AC. Influence of dissolved oxygen and shear conditions on clavulanic acid production by Streptomyces clavuligerus. Bioprocess Biosyst Eng. 2005;27(2):99–104. 22. Rodrigues MI, Iemma AF. Experimental Design and Process Optimization. Florida: CRC Press; 2014. 23. Bird AE, Bellis JM, Gasson BC. Spectrophotometric assay of clavulanic acid by reaction with imidazole. Analyst. 1982;107:1241–1245. 24. Busby RW, Chang MDT, Busby RC, Wimp J, Townsend CA. Expression and purification of 2 isozymes of clavaminate synthase and initial characterization of the iron-binding site – general error analysis in polymerase chain-reaction amplification. J Biol Chem. 1995;270(9):4262–4269. 25. Kanehisa M, Goto S, Sato Y, Kawashima M, Furumichi M, Tanabe M. Data, information, knowledge and principle: back to metabolism in KEGG. Nucleic Acids Res. 2014;42(D1). D199–D205. 26. Ozcengiz G, Demain AL. Recent advances in the biosynthesis of penicillins, cephalosporins and clavams and its regulation. Biotechnol Adv. 2013;31(2):287–311. 27. Sanchez L, Brana AF. Cell density influences antibiotic biosynthesis in Streptomyces clavuligerus. Microbiology. 1996;142:1209–1220. 28. Neves AA, Vieira LM, Menezes JC. Effects of preculture variability on clavulanic acid fermentation. Biotechnol Bioeng. 2001;72(6):628–633. 29. Mayer AF, Deckwer WD. Simultaneous production and decomposition of clavulanic acid during Streptomyces http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 http://refhub.elsevier.com/S1517-8382(17)30789-X/sbref0160 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