Improved production of A40926 by Nonomuraea sp. through deletion of a pathway-specific acetyltransferase

Sosio, Margherita; Canavesi, Augusto; Stinchi, Sofia; Donadio, Stefano

doi:10.1007/s00253-010-2579-2

Cited by 21 publications

(28 citation statements)

References 27 publications

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“…strain ATCC 39727 has been successfully obtained using different growth conditions (33)(34)(35)(36). One example of successful genetic manipulation has also been reported, since deletion of dbv23, responsible for adding the acetyl group to the mannose moiety, led to a 2-fold increase in A40926 yield (8). In our studies, overexpression of dbv3 also resulted in higher antibiotic production, providing a potentially useful example of knowledge-based strain improvement.…”

Section: Discussionmentioning

confidence: 64%

“…Further tailoring steps include halogenation, glycosylation, oxidation, methylation, acetylation, and acylation (5). The A40926 components differ by the type of N-acyl chain attached to the glucuronic acid moiety and by the presence or absence of an O-linked acetyl residue at position 6 of the mannose (6)(7)(8). The form with the acetylated mannose was proposed to be the final biosynthetic product, which in turn exerts an inhibitory effect on A40926 production by a yet unknown mechanism (8).…”

mentioning

confidence: 99%

“…The A40926 components differ by the type of N-acyl chain attached to the glucuronic acid moiety and by the presence or absence of an O-linked acetyl residue at position 6 of the mannose (6)(7)(8). The form with the acetylated mannose was proposed to be the final biosynthetic product, which in turn exerts an inhibitory effect on A40926 production by a yet unknown mechanism (8). Detailed studies of A40926 biosynthesis and its regulation will be crucial for the development of rational approaches towards overproduction of the dalbavancin precursor.…”

mentioning

confidence: 99%

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Two Master Switch Regulators Trigger A40926 Biosynthesis in Nonomuraea sp. Strain ATCC 39727

Grasso

Maffioli²,

Sosio³

et al. 2015

J Bacteriol

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The actinomycete Nonomuraea sp. strain ATCC 39727 produces the glycopeptide A40926, the precursor of dalbavancin. Biosynthesis of A40926 is encoded by the dbv gene cluster, which contains 37 protein-coding sequences that participate in antibiotic biosynthesis, regulation, immunity, and export. In addition to the positive regulatory protein Dbv4, the A40926-biosynthetic gene cluster encodes two additional putative regulators, Dbv3 and Dbv6. Independent mutations in these genes, combined with bioassays and liquid chromatography-mass spectrometry (LC-MS) analyses, demonstrated that Dbv3 and Dbv4 are both required for antibiotic production, while inactivation of dbv6 had no effect. In addition, overexpression of dbv3 led to higher levels of A40926 production. Transcriptional and quantitative reverse transcription (RT)-PCR analyses showed that Dbv4 is essential for the transcription of two operons, dbv14-dbv8 and dbv30-dbv35, while Dbv3 positively controls the expression of four monocistronic transcription units (dbv4, dbv29, dbv36, and dbv37) and of six operons (dbv2-dbv1, dbv14-dbv8, dbv17-dbv15, dbv21-dbv20, dbv24-dbv28, and dbv30-dbv35). We propose a complex and coordinated model of regulation in which Dbv3 directly or indirectly activates transcription of dbv4 and controls biosynthesis of 4-hydroxyphenylglycine and the heptapeptide backbone, A40926 export, and some tailoring reactions (mannosylation and hexose oxidation), while Dbv4 directly regulates biosynthesis of 3,5-dihydroxyphenylglycine and other tailoring reactions, including the four cross-links, halogenation, glycosylation, and acylation. IMPORTANCEThis report expands knowledge of the regulatory mechanisms used to control the biosynthesis of the glycopeptide antibiotic A40926 in the actinomycete Nonomuraea sp. strain ATCC 39727. A40926 is the precursor of dalbavancin, approved for treatment of skin infections by Gram-positive bacteria. Therefore, understanding the regulation of its biosynthesis is also of industrial importance. So far, the regulatory mechanisms used to control two other similar glycopeptides (balhimycin and teicoplanin) have been elucidated, and beyond a common step, different clusters seem to have devised different strategies to control glycopeptide production. Thus, our work provides one more example of the pitfalls of deducing regulatory roles from bioinformatic analyses only, even when analyzing gene clusters directing the synthesis of structurally related compounds. T he glycopeptide antibiotic A40926 (Fig. 1A) is the precursor for dalbavancin, a semisynthetic lipoglycopeptide approved for clinical use in 2014 by the U.S. Food and Drug Administration to treat acute bacterial skin and skin structure infections caused by bacteria, such as Staphylococcus aureus (methicillin-susceptible and methicillin-resistant strains) and Streptococcus pyogenes. Compared with the structurally related glycopeptide teicoplanin, dalbavancin possesses better potency and pharmacokinetic properties.A40926 is produced by the actinomycete Nonomurae...

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Section: Discussionmentioning

confidence: 64%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Two Master Switch Regulators Trigger A40926 Biosynthesis in Nonomuraea sp. Strain ATCC 39727

Grasso

Maffioli²,

Sosio³

et al. 2015

J Bacteriol

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“…Consequently, approximately double amount of the antibiotic produced by a mutant strain with deletion of gene dbv23 encoding a pathway‐specific acetyltransferase from the gene cluster dbv of this Nonomuraea sp. was revealed . This study manifests the impact of nutrient compositions and growing stages that direct the cellular biosynthesis of secondary metabolites, which are regulated by central dogma of microbial cell itself.…”

Section: Antimicrobial Substancesmentioning

confidence: 88%

The genus Nonomuraea: A review of a rare actinomycete taxon for novel metabolites

Sungthong

Nakaew

2014

J. Basic Microbiol.

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The genus Nonomuraea is a rare actinomycete taxon with a long taxonomic history, while its generic description was recently emended. The genus is less known among the rare actinomycete genera as its taxonomic position was revised several times. It can be found in diverse ecological niches, while most of its member species were isolated from soil samples. However, new trends to discover the genus in other habitats are increasing. Generic abundance of the genus was found to be dependent on geographical changes. Novel sources together with selective and invented isolation techniques might increase a chance to explore the genus and its novel candidates. Interestingly, some of its members have been revealed as a valuable source of novel metabolites for medical and industrial purposes. Broad-range of potent bioactive compounds including antimicrobial, anticancer, and antipsychotic substances, broad-spectrum antibiotics and biocatalysts can be synthesized by the genus. In order to investigate biosynthetic pathways of the bioactive compounds and self-resistant mechanisms to these compounds, the links from genes to metabolites have yet been needed for further discovery and biotechnological development of the genus Nonomuraea.

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“…1)[3,8]. Since compound 1 was conveniently converted intocompound 2 during extraction and purification, A40926 started to indicate compound 2 only.…”

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confidence: 99%

High-yield production of lipoglycopeptide antibiotic A40926 using a mutant strain Nonomuraea sp. DP-13 in optimized medium

Chen

Zhang

et al. 2016

Preparative Biochemistry & Biotechnology

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The lipoglycopeptide antibiotic A40926 produced by Nonomuraea sp. is a complex of structurally related components differing in the fatty acid moiety. Besides showing an intrinsic antibacterial activity, A40926 is the precursor of the semisynthetic antibiotic Dalvance. In this work, A40926 production by a mutant strain Nonomuraea sp. DP-13 was investigated. It was found that A40926 production was markedly promoted by using poorly assimilated carbon source maltodextrin and nitrogen source soybean meal. Addition of Cu(2+) resulted in a stimulation of A40926 production, but Co(2+) had an inhibitory effect. L-Leucine addition greatly improved total A40926 production and modified the complex composition toward factor B0. An optimized production medium IM-3 was developed and a maximum A40926 production of 1096 mg/L was obtained in the 10-L fermenter. This was the highest A40926 productivity so far reported.

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Improved production of A40926 by Nonomuraea sp. through deletion of a pathway-specific acetyltransferase

Cited by 21 publications

References 27 publications

Two Master Switch Regulators Trigger A40926 Biosynthesis in Nonomuraea sp. Strain ATCC 39727

Two Master Switch Regulators Trigger A40926 Biosynthesis in Nonomuraea sp. Strain ATCC 39727

The genus Nonomuraea: A review of a rare actinomycete taxon for novel metabolites

High-yield production of lipoglycopeptide antibiotic A40926 using a mutant strain Nonomuraea sp. DP-13 in optimized medium

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