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Data set of in silico simulation for the production of clavulanic acid and cephamycin C by Streptomyces clavuligerus using a genome scale metabolic model.

ABSTRACT: Streptomyces clavuligerus (S. clavuligerus) is a Gram-positive bacterium which produced clavulanic acid (CA) and cephamycin C (CephC). In this data article, a curated genome scale metabolic model of S. clavuligerus is presented. A total of eighteen objective functions were evaluated for a better representation of CA and CephC production by S. clavuligerus. The different objective functions were evaluated varying the weighting factors of CA and CephC between 0, 1 y 2, whereas for the case of biomass the weight factor was varied between 1 and 2. A robustness analysis, by mean of flux balance analysis, showed five different metabolic phenotypes of S. clavuligerus as a function of oxygen uptake: (I) and (II) biomass production, (III) biomass and CephC production, (IV) simultaneous production of biomass, CA and CephC and (V) production of biomass and CA. Data of shadow prices and reduced cost are also presented.

SUBMITTER: Gomez-Ceron S

PROVIDER: S-EPMC6538926 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Clavulanic acid (CA) is the preferred clinical drug for the treatment of infections by β-lactam antibiotic-resistant bacteria. CA is produced by Streptomyces clavuligerus, and although there have been many reports on the effects of carbon and nitrogen sources on CA production, the mechanisms involved remain unclear. In this study, we found that CA accumulation in S. clavuligerus F613-1 was increased significantly in MH medium, which is rich in organic nitrogen, compared with that in ML medium, which contains half the amount of organic nitrogen present in MH medium. Transcriptome analysis revealed that genes involved in CA biosynthesis, such as ceas1, ceas2, bls1, bls2, cas2, pah2, gcaS, and cad, and arginine biosynthesis, such as argB, argC, argD, argG, argH, argJ, and argR, were upregulated under rich organic nitrogen. Metabolome data revealed notable differences between cultures of F613-1 grown in MH and ML media with regard to levels of key intracellular metabolites, most of which are involved in arginine metabolic pathways, including arginine, glutamine, and glutamic acid. Additionally, supplementation of ML medium with arginine, glutamine, or glutamic acid resulted in increased CA production by S. clavuligerus F613-1. Our results indicate that rich organic nitrogen mainly affects CA biosynthesis by increasing the levels of amino acids associated with the arginine metabolic pathway and activating the expression of the CA biosynthetic gene cluster. These findings provide important insights for improving medium optimization and engineering of S. clavuligerus F613-1 for high-yield production of CA. IMPORTANCE The bacterium Streptomyces clavuligerus is used for the industrial production of the broad-spectrum β-lactamase inhibitor clavulanic acid (CA). However, much remains unknown about the factors which affect CA yields. We investigated the effects of different levels of organic nitrogen on CA production. Our analyses indicate that higher organic nitrogen levels were associated with increased CA yields and increased levels of arginine biosynthesis. Further analyses supported the relationship between arginine metabolism and CA production and demonstrated that increasing the levels of arginine or associated amino acids could boost CA yields. These findings suggest approaches for improving the production of this clinically important antibiotic.

Dataset Information

Data set of in silico simulation for the production of clavulanic acid and cephamycin C by Streptomyces clavuligerus using a genome scale metabolic model.

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