BackgroundLysine plays an important role in Streptomyces clavuligerus metabolism; it takes part in its catabolism, via cadaverine, and in its secondary metabolism, in which lysine is converted via 1-piperideine-6-carboxylate to alpha-aminoadipic acid, a beta-lactam antibiotic precursor. The role of lysine as an enhancer of cephamycin C production, when added to production medium at concentrations above 50 mmol l-1, has already been reported in the literature, with some studies attributing a positive influence to multifunctional diamines, among other compounds. However, there is a lack of research on the combined effect of these compounds on antibiotic production.ResultsResults from experimental design-based tests were used to conduct response surface-based optimization studies in order to investigate the synergistic effect of combining lysine with cadaverine, putrescine, 1,3-diaminopropane, or alpha-aminoadipic acid on cephamycin C volumetric production. Lysine combined with cadaverine influenced production positively, but only at low lysine concentrations. On the whole, higher putrescine concentrations (0.4 g l-1) affected negatively cephamycin C volumetric production. In comparison to culture media containing only lysine as additive, combinations of this amino acid with alpha-aminoadipic acid or 1,3-diaminopropane increased cephamycin C production by more than 100%.ConclusionThis study demonstrated that different combinations of lysine with diamines or lysine with alpha-aminoadipic acid engender significant differences with respect to antibiotic volumetric production, with emphasis on the benefits observed for lysine combined with alpha-aminoadipic acid or 1,3-diaminopropane. This increase is explained by mathematical models and demonstrated by means of bioreactor cultivations. Moreover, it is consistent with the positive influence of these compounds on lysine conversion to alpha-aminoadipic acid, a limiting step in cephamycin C production.

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Streptomyces clavuligerus produces simultaneously cephamycin C (CephC) and clavulanic acid (CA). Adding 1,3-diaminopropane to culture medium stimulates production of beta-lactam antibiotics. However, there are no studies on the influence of this diamine on coordinated production of CephC and CA. This study indicates that 1,3-diaminopropane can dissociate CephC and CA productions. Results indicated that low diamine concentrations (below 1.25 g l(-1)) in culture medium increased CA production by 200%, but not that of CephC. Conversely, CephC production increased by 300% when 10 g l(-1) 1,3-diaminopropane was added to culture medium. Addition of just L-lysine (18.3 g l(-1)) to culture medium increased both biocompounds. On the other hand, while L-lysine plus 7.5 g l(-1) 1,3-diaminopropane increased volumetric production of CephC by 1100%, its impact on CA production was insignificant. The combined results suggest that extracellular concentration of 1,3-diaminopropane may trigger the dissociation of CephC and CA biosynthesis in S. clavuligerus.

The aim of this work was to compare the composition of a complex and soluble culture medium to eight other media described in the literature through the batch cultivation in a conventional bench-scale bioreactor for the production of cephamycin C by a wild strain of Streptomyces clavuligerus. The proposed medium resulted in an antibiotic production 1.5 to 7.5 times higher than the other culture media.

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RESUMO -Streptomyces clavuligerus produz vários biocompostos de uso terapêutico, como os beta-lactâmicos ácido clavulânico e cefamicina C, e os não beta-lactâmicos holomicina e tunicamicina. Holomicina é conhecida por inibir a síntese de RNA polimerase de bactérias resistentes a rifamicina e é produzida em baixas concentrações (6 a 8 mgL -1 ) pela cepa selvagem (ATCC 27064) sob condições favoráveis à produção de beta-lactâmicos. Cultivos em biorreator convencional operado em batelada mostraram que a combinação de maltose e lisina promoveu a produção de cefamicina C e ácido clavulânico (90 a 100 mgL -1 ), sem produção de holomicina, e a mesma combinação (maltose e lisina) adicionada de glutamato estimulou a produção de holomicina (95 a 110 mgL -1 ), com produção de cefamicina C ou ácido clavulânico cerca de 65% menor para ambos. Os dados obtidos permitiram estimar parâmetros cinéticos e estequiométricos dos processos por meio de modelagem e simulação.