Dissociation of cephamycin C and clavulanic acid biosynthesis by 1,3-diaminopropane in<i>Streptomyces clavuligerus</i>

Leite, Carla Andréa; Cavallieri, André Pastrelo; Baptista, Amanda Salvador; Araujo, Maria Lucia Gonsales da Costa

doi:10.1093/femsle/fnv215

Cited by 7 publications

(4 citation statements)

References 26 publications

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“…In contrast, the glycerol feeding strongly enhanced CA as previously reported [21]. Interestingly, the variable concentration of 1,3-diaminopropane in the culture changes that connected production in the favor of either compound [13,22].…”

Section: Introductionsupporting

confidence: 80%

Homologous expression of lysA encoding diaminopimelic acid (DAP) decarboxylase reveals increased antibiotic production in Streptomyces clavuligerus

Otur

Kurt‐Kızıldoğan

2019

Braz J Microbiol

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lysA gene encoding meso-diaminopimelic acid (DAP) decarboxylase enzyme that catalyzes L-lysine biosynthesis in the aspartate pathway in Streptomyces clavuligerus was overexpressed, and its effects on cephamycin C (CephC), clavulanic acid (CA), and tunicamycin productions were investigated. Multicopy expression of lysA gene under the control of glpF promoter (glpFp) in S. clavuligerus pCOlysA led to higher expression levels ranging from 2-to 6-fold increase at both lysA gene and CephC biosynthetic gene cluster at T 36 and T 48 of TSBG fermentation. These results accorded well with CephC production. Thus, 1.86-and 3.14-fold higher volumetric as well as 1.26-and 1.71-fold increased specific CephC yields were recorded in S. clavuligerus pCOlysA in comparison with the wild-type and its control strain, respectively, at 48th h. Increasing the expression of lysA provided 4.3 times more tunicamycin yields in the recombinant strain. These findings suggested that lysA overexpression in S. clavuligerus made the strain more productive for CephC and tunicamycin. The results also supported the presence of complex interactions among antibiotic biosynthesis pathways in S. clavuligerus.

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Section: Introductionsupporting

confidence: 80%

Homologous expression of lysA encoding diaminopimelic acid (DAP) decarboxylase reveals increased antibiotic production in Streptomyces clavuligerus

Otur

Kurt‐Kızıldoğan

2019

Braz J Microbiol

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“…Three phosphate systems with different concentrations (0, 2.5 × 10 −3 , and 4 mM) were established in this study; however, the bacterial density and target product production in the medium without phosphate were significantly higher than those in the low-phosphate concentration and high-phosphate concentration systems. These results demonstrate that butenyl-spinosyn production is also highly sensitive to phosphate control, in contrast to the lower sensitivity of other classes of secondary metabolites, such as orthosomycin antibiotics ( Zhu et al., 2007 ) or cephalosporins ( Leite et al., 2016 ), that are only inhibited at high phosphate concentrations (20–100 mM).…”

Section: Discussionmentioning

confidence: 81%

SenX3-RegX3, an Important Two-Component System, Regulates Strain Growth and Butenyl-spinosyn Biosynthesis in Saccharopolyspora pogona

Rang

Chen

et al. 2020

iScience

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Summary Butenyl-spinosyn produced by Saccharopolyspora pogona exhibits strong insecticidal activity and a broad pesticidal spectrum. Currently, important functional genes involved in butenyl-spinosyn biosynthesis remain unknown, which leads to difficulty in efficient understanding of its regulatory mechanism and improving its production by metabolic engineering. Here, we present data supporting a role of the SenX3-RegX3 system in regulating the butenyl-spinosyn biosynthesis. EMSAs and qRT-PCR demonstrated that RegX3 positively controls butenyl-spinosyn production in an indirect way. Integrated proteomic and metabolomic analysis, regX3 deletion not only strengthens the basal metabolic ability of S. pogona in the mid-growth phase but also promotes the flow of the acetyl-CoA produced via key metabolic pathways into the TCA cycle rather than the butenyl-spinosyn biosynthetic pathway, which ultimately leads to continued growth but reduced butenyl-spinosyn production. The strategy demonstrated here may be valuable for revealing the regulatory role of the SenX3-RegX3 system in the biosynthesis of other natural products.

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“…Apart from S. clavuligerus , Streptomyces jumonjinensis and Streptomyces katsurahamanus are the only other species known to produce CA along with Ceph-C (Ward and Hodgson, 1993; Jensen, 2012). In addition, CA production in S. clavuligerus generally occurs in conjunction with Ceph-C (Romero et al, 1984; Jensen and Paradkar, 1999), even though both metabolites are products of distinct biosynthetic pathways (Hamed et al, 2013). As in the case of other Actinobacterial SMs (van der Heul et al, 2018), the regulation of CA production in S. clavuligerus is complex and involves cluster-situated regulators, global mechanisms, and signaling cascades (Liras et al, 2008; Song et al, 2010a; Paradkar, 2013; Ferguson et al, 2016; Álvarez-Álvarez et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism

et al. 2019

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Clavulanic acid is a bacterial specialized metabolite, which inhibits certain serine β-lactamases, enzymes that inactivate β-lactam antibiotics to confer resistance. Due to this activity, clavulanic acid is widely used in combination with penicillin and cephalosporin (β-lactam) antibiotics to treat infections caused by β-lactamase-producing bacteria. Clavulanic acid is industrially produced by fermenting Streptomyces clavuligerus, as large-scale chemical synthesis is not commercially feasible. Other than S. clavuligerus, Streptomyces jumonjinensis and Streptomyces katsurahamanus also produce clavulanic acid along with cephamycin C, but information regarding their genome sequences is not available. In addition, the Streptomyces contain many biosynthetic gene clusters thought to be “cryptic,” as the specialized metabolites produced by them are not known. Therefore, we sequenced the genomes of S. jumonjinensis and S. katsurahamanus, and examined their metabolomes using untargeted mass spectrometry along with S. clavuligerus for comparison. We analyzed the biosynthetic gene cluster content of the three species to correlate their biosynthetic capacities, by matching them with the specialized metabolites detected in the current study. It was recently reported that S. clavuligerus can produce the plant-associated metabolite naringenin, and we describe more examples of such specialized metabolites in extracts from the three Streptomyces species. Detailed comparisons of the biosynthetic gene clusters involved in clavulanic acid (and cephamycin C) production were also performed, and based on our analyses, we propose the core set of genes responsible for producing this medicinally important metabolite.

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Dissociation of cephamycin C and clavulanic acid biosynthesis by 1,3-diaminopropane inStreptomyces clavuligerus

Cited by 7 publications

References 26 publications

Homologous expression of lysA encoding diaminopimelic acid (DAP) decarboxylase reveals increased antibiotic production in Streptomyces clavuligerus

Homologous expression of lysA encoding diaminopimelic acid (DAP) decarboxylase reveals increased antibiotic production in Streptomyces clavuligerus

SenX3-RegX3, an Important Two-Component System, Regulates Strain Growth and Butenyl-spinosyn Biosynthesis in Saccharopolyspora pogona

Comparative Genomics and Metabolomics Analyses of Clavulanic Acid-Producing Streptomyces Species Provides Insight Into Specialized Metabolism

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