Biosynthesis of the Peptide Antibiotic Feglymycin by a Linear Nonribosomal Peptide Synthetase Mechanism

Gonsior, Melanie; Mühlenweg, Agnes; Tietzmann, Marcel; Rausch, Saskia; Poch, Annette; Süssmuth, Roderich D.

doi:10.1002/cbic.201500432

Cited by 21 publications

(12 citation statements)

References 46 publications

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“…For example, there is an NRPS-containing BGC in S. jumonjinensis that is 100% similar to the BGC in Streptomyces sp. DSM 11171, which produces the antiviral metabolite feglymycin (Supplementary Table S4; Gonsior et al, 2015). We also identified indole-associated BGCs in S. clavuligerus and S. jumonjinensis (Supplementary Table S4), which are similar to the one from Streptomyces sp.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…DSM 11171 (Figure 1) encodes for a 13-mer peptide antibiotic acting on bacterial cell wall biosynthesis by inhibiting MurA and MurC. Albeit the structure and the mode of action of feglymycin differs from the ones of GPAs, feglymycin BGC shares a high level of similarity with GPA BGCs (Gonsior et al, 2015;Yushchuk et al, 2020a), including the presence of vanRS-like genes -fegM and fegN.…”

Section: Updating the Glycopeptide Resistance Paradigm For The Gpa-producing Strains: Van Genes And Their Organization In Known And Putatmentioning

confidence: 99%

Glycopeptide Antibiotic Resistance Genes: Distribution and Function in the Producer Actinomycetes

2020

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Glycopeptide antibiotics (GPAs) are considered drugs of "last resort" for the treatment of life-threatening infections caused by relevant Gram-positive pathogens (enterococci, staphylococci, and clostridia). Driven by the issue of the never-stopping evolution of bacterial antibiotic resistance, research on GPA biosynthesis and resistance is developing fast in modern "post-genomic" era. It is today widely accepted that resistance mechanisms emerging in pathogens have been acquired from the soil-dwelling antibiotic-producing actinomycetes, which use them to avoid suicide during production, rather than being orchestrated de novo by pathogen bacteria upon continued treatment. Actually, more and more genomes of GPA producers are being unraveled, carrying a broad collection of differently arranged GPA resistance (named van) genes. In the producer actinomycetes, van genes are generally associated with the antibiotic biosynthetic gene clusters (BGCs) deputed to GPA biosynthesis, being probably transferred/arranged together, favoring a possible co-regulation between antibiotic production and self-resistance. GPA BGC-associated van genes have been also found mining public databases of bacterial genomic and metagenomic sequences. Interestingly, some BGCs for antibiotics, seemingly unrelated to GPAs (e.g., feglymycin), carry van gene homologues. Herein, we would like to cover the recent advances on the distribution of GPA resistance genes in genomic and metagenomics datasets related to GPA potential/proved producer microorganisms. A thorough understanding of GPA resistance in the producing microorganisms may prove useful in the future surveillance of emerging mechanisms of resistance to this clinically relevant antibiotic class.

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“…7, left panel). In contrast, Dbv6 clusters together with response www.nature.com/scientificreports www.nature.com/scientificreports/ regulators associated with gene clusters for kistamicin A (from a Nonomuraea sp 26 ) and for feglymycin (from a Streptomyces sp 27 .). Kistamicin A is a partially cross-linked heptapeptide sharing some amino acid residues with glycopeptide antibiotics, whereas feglymycin is a linear tridecapeptide containing several HPG and DPG residues.…”

Section: Dbv6 and Dbv22 Are Unrelated To Other Tcss Associated With Omentioning

confidence: 99%

A Two-Component regulatory system with opposite effects on glycopeptide antibiotic biosynthesis and resistance

Alduina

Tocchetti²,

Costa

et al. 2020

Sci Rep

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The glycopeptide A40926, produced by the actinomycete Nonomuraea gerenzanensis, is the precursor of dalbavancin, a second-generation glycopeptide antibiotic approved for clinical use in the USA and Europe in 2014 and 2015, respectively. The final product of the biosynthetic pathway is an O-acetylated form of A40926 (acA40926). Glycopeptide biosynthesis in N. gerenzanensis is dependent upon the dbv gene cluster that encodes, in addition to the two essential positive regulators Dbv3 and Dbv4, the putative members of a two-component signal transduction system, specifically the response regulator Dbv6 and the sensor kinase Dbv22. The aim of this work was to assign a role to these two genes. Our results demonstrate that deletion of dbv22 leads to an increased antibiotic production with a concomitant reduction in glycopeptide resistance. Deletion of dbv6 results in a similar phenotype, although the effects are not as strong as in the Δdbv22 mutant. Consistently, quantitative RT-PCR analysis showed that Dbv6 and Dbv22 negatively regulate the regulatory genes (dbv3 and dbv4), as well as some dbv biosynthetic genes (dbv23 and dbv24), whereas Dbv6 and Dbv22 positively regulate transcription of the single, cluster-associated resistance gene. Finally, we demonstrate that exogenously added acA40926 and its precursor A40926 can modulate transcription of dbv genes but with an opposite extent: A40926 strongly stimulates transcription of the Dbv6/Dbv22 target genes while acA40926 has a neutral or negative effect on transcription of those genes. We propose a model in which glycopeptide biosynthesis in N. gerenzanensis is modulated through a positive feedback by the biosynthetic precursor A40926 and a negative feedback by the final product acA40926. In addition to previously reported control systems, this sophisticated control loop might help the producing strain cope with the toxicity of its own product. This work, besides leading to improved glycopeptide producing strains, enlarges our knowledge on the regulation of glycopeptide biosynthesis in actinomycetes, setting N. gerenzanensis and its two-component system Dbv6-Dbv22 apart from other glycopeptide producers. The glycopeptide antibiotic A40926 (Fig. 1A) is the precursor for dalbavancin (Fig. 1B), a semisynthetic lipoglycopeptide clinically used for treatment of acute skin infections caused by methicillin-susceptible and methicillin-resistant Staphylococcus aureus and Streptococcus pyogenes. A40926 is produced by the actinomycete N. gerenzanensis as a complex of related compounds, differing mostly by the type of N-acyl chain attached to the glucuronic acid moiety. The core structure of A40926 consists of a heptapeptide containing the proteinogenic amino acid tyrosine and the non-proteinogenic amino acids 3,5-dihydroxyphenylglycine (DPG) and 4-hydroxyphenylglycine (HPG). The heptapeptide is assembled by a nonribosomal peptide synthetase (NRPS) and modified by the action of various enzymes: four oxygenases, one halogenase, one hydroxylase, two glycosyltransferases, one hexose ox...

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Biosynthesis of the Peptide Antibiotic Feglymycin by a Linear Nonribosomal Peptide Synthetase Mechanism

Cited by 21 publications

References 46 publications

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

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

Glycopeptide Antibiotic Resistance Genes: Distribution and Function in the Producer Actinomycetes

A Two-Component regulatory system with opposite effects on glycopeptide antibiotic biosynthesis and resistance

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