A regulatory gene (ccaR) required for cephamycin and clavulanic acid production in Streptomyces clavuligerus: amplification results in overproduction of both beta-lactam compounds

Pérez-Llarena, Francisco José; Liras, Paloma; Rodrı́guez-Garcı́a, Antonio; Martı́n, Juan F.

doi:10.1128/jb.179.6.2053-2059.1997

Cited by 146 publications

(139 citation statements)

References 41 publications

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“…Such ''superclustering'' would be expected for gene clusters that direct the production of metabolites that act synergistically to benefit the producing organism (19,20). In addition, the production of both cephamycin and clavulanic acid in S. clavuligerus is controlled principally by the ccaR (dclX) gene, which codes for an OmpR-like transcriptional regulator, and is located within the cephamycin cluster (21,22). In contrast, the clavam cluster is at least 20-30 kb away from the cephamycin͞clavulanic acid clusters on the S. clavuligerus chromosome, and the regulation of clavam production is distinct from the coregulated production of cephamycins and clavulanic acid (23)(24)(25).…”

mentioning

confidence: 99%

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

Challis

Hopwood

2003

Proc. Natl. Acad. Sci. U.S.A.

544

398

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In this article we briefly review theories about the ecological roles of microbial secondary metabolites and discuss the prevalence of multiple secondary metabolite production by strains of Streptomyces, highlighting results from analysis of the recently sequenced Streptomyces coelicolor and Streptomyces avermitilis genomes. We address this question: Why is multiple secondary metabolite production in Streptomyces species so commonplace? We argue that synergy or contingency in the action of individual metabolites against biological competitors may, in some cases, be a powerful driving force for the evolution of multiple secondary metabolite production. This argument is illustrated with examples of the coproduction of synergistically acting antibiotics and contingently acting siderophores: two well-known classes of secondary metabolite. We focus, in particular, on the coproduction of ␤-lactam antibiotics and ␤-lactamase inhibitors, the coproduction of type A and type B streptogramins, and the coregulated production and independent uptake of structurally distinct siderophores by species of Streptomyces. Possible mechanisms for the evolution of multiple synergistic and contingent metabolite production in Streptomyces species are discussed. It is concluded that the production by Streptomyces species of two or more secondary metabolites that act synergistically or contingently against biological competitors may be far more common than has previously been recognized, and that synergy and contingency may be common driving forces for the evolution of multiple secondary metabolite production by these sessile saprophytes.

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mentioning

confidence: 99%

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

Challis

Hopwood

2003

Proc. Natl. Acad. Sci. U.S.A.

544

398

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“…A similar super-cluster for cephamycin and clavulanic acid was found in S. clavuligerus, 55 where the two metabolites function synergistically as an antibiotic and a b-lactamase inhibitor, respectively, and their biosynthesis is regulated by the SARP gene ccaR. 56 …”

Section: Biosynthesis Of Lankacidin and Lankamycinmentioning

confidence: 61%

Giant linear plasmids in Streptomyces: a treasure trove of antibiotic biosynthetic clusters

Kinashi

2010

J Antibiot

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Many giant linear plasmids have been isolated from Streptomyces by using pulsed-field gel electrophoresis and some of them were found to carry an antibiotic biosynthetic cluster(s); SCP1 carries biosynthetic genes for methylenomycin, pSLA2-L for lankacidin and lankamycin, and pKSL for lasalocid and echinomycin. Accumulated data suggest that giant linear plasmids have played critical roles in genome evolution and horizontal transfer of secondary metabolism. In this review, I summarize typical examples of giant linear plasmids whose involvement in antibiotic production has been studied in some detail, emphasizing their finding processes and interaction with the host chromosomes. A hypothesis on horizontal transfer of secondary metabolism involving giant linear plasmids is proposed at the end.

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“…Unlike S. clavuligerus, S. exfoliatus is not known to produce any β-lactam metabolites. Perez-Llarena et al (1997a) have also reported the presence of a gene in S. clavuligerus that encodes a putative protein called BLP, for BLIP-like protein. The amino acid sequence of BLP shows significant similarity to BLIP, with 29n2 % identical and an additional 27n6% functionally conserved residues.…”

Section: Abbreviations : Abc Atp-binding Cassette ; Blip β-Lactamasmentioning

confidence: 99%

“…The resulting 3876 bp sequence can be found in GenBank, accession number M34538. The blp gene is flanked on the 5h end by the ccaR and orf11 and on the 3h end by the genes encoding early enzymes of cephamycin biosynthesis (Perez-Llarena et al, 1997a). In contrast, the bli gene is flanked on the 5h end by an ORF, bliup1, located 388 bp upstream and oriented diver- gently to the bli gene.…”

Section: Examination Of the Dna Sequence Flanking The Bli Genementioning

confidence: 99%

Construction and analysis of β-lactamase-inhibitory protein (BLIP) non-producer mutants of Streptomyces clavuligerus The GenBank accession number for the sequence determined in this work is M34538.

2001

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The gene encoding BLIP, a beta-lactamase-inhibitory protein, was disrupted in wild-type Streptomyces clavuligerus and in a clavulanic acid non-producing mutant. The resulting BLIP mutant and BLIP/clavulanic acid double mutant showed no residual proteinaceous β-lactamase-inhibitory activity, indicating that only a single β-lactamase-inhibitory protein exists in S. clavuligerus. The lack of any proteinaceous β-lactamase-inhibitory activity in the bli and bli/claR mutants also indicates that BLP, the BLIP-like protein, encoded by S.clavuligerus does not possess β-lactamase-inhibitory activity despite its similarity to BLIP. The bli mutant and the bli/claR double mutant did not show any aberrant growth morphology, sporulation defects, or alterations in cephamycin C production or penicillin G resistance when compared to wildtype S. clavuligerus or to the claR single mutant. Mutants bearing the bli gene disruption did show an elevated level of production of clavam-2-carboxylate and hydroxymethyl clavam as well as clavulanic acid. This phenomenon was observed in the middle stages of production of these clavams but was not detected during maximum production. The production of BLIP was also determined to be down-regulated in a ccaR mutant, lacking the pathwayspecific transcriptional regulator required for production of cephamycin C and clavulanic acid. Sequencing of the regions flanking the bli gene showed the presence of a partial open reading frame that encodes a DNA-binding protein, and several open reading frames apparently involved in the production of an ABC transporter.

show abstract

A regulatory gene (ccaR) required for cephamycin and clavulanic acid production in Streptomyces clavuligerus: amplification results in overproduction of both beta-lactam compounds

Cited by 146 publications

References 41 publications

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species

Giant linear plasmids in Streptomyces: a treasure trove of antibiotic biosynthetic clusters

Construction and analysis of β-lactamase-inhibitory protein (BLIP) non-producer mutants of Streptomyces clavuligerus The GenBank accession number for the sequence determined in this work is M34538.

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