Glycopeptide antibiotic biosynthesis

Yim, Grace; Thaker, Maulik; Koteva, Kalinka; Wright, Gerard D.

doi:10.1038/ja.2013.117

Cited by 167 publications

(234 citation statements)

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“…1), with vancomycin and teicoplanin as representative members -there is a need to characterise NRPS biosynthesis in order to explore the possibilities for compound development through redesigning the corresponding biosynthetic machinery. [1][2][3][4] In this regard, GPAs are perfect examples: total synthesis is highly challenging, meaning that all GPAs in clinical use stem from bacterial production in vivo and modified GPAs generated via total synthesis are not always accessible for the use in clinics. 4,5 The main reasons for this synthetic complexity are the high content of racemisation-prone phenylglycine residues as well as the highly crosslinked structure of GPAs (vancomycin:…”

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confidence: 99%

“…[1][2][3][4] In this regard, GPAs are perfect examples: total synthesis is highly challenging, meaning that all GPAs in clinical use stem from bacterial production in vivo and modified GPAs generated via total synthesis are not always accessible for the use in clinics. 4,5 The main reasons for this synthetic complexity are the high content of racemisation-prone phenylglycine residues as well as the highly crosslinked structure of GPAs (vancomycin:, which is formed by cytochrome P450 (Oxy) enzymes that interact with the unique NRPS domain found in GPA biosynthesis, the X-domain. 4,6,7 Fig.…”

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confidence: 99%

“…4,5 The main reasons for this synthetic complexity are the high content of racemisation-prone phenylglycine residues as well as the highly crosslinked structure of GPAs (vancomycin:…”

mentioning

confidence: 99%

“…[1][2][3][4] Due to the modular structure of nonribosomal peptide synthetases (NRPSs) -comprising repeating domains performing specific catalytic functions -and their non-dependence on the ribosome, NRPS assembly lines are able to synthesise peptides from a wide range of amino acids.…”

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confidence: 99%

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A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis

et al. 2018

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abc Non-ribosomal peptides contain an array of amino acid building blocks that can present challenges for the synthesis of important intermediates. Here, we report the synthesis of glycopeptide antibiotic (GPA) thioester peptides that retains the crucial stereochemical purity of the terminal phenylglycine residue, which we show is essential for the enzymatic GPA cyclisation cascade.Non-ribosomal peptide synthesis is central to the biosynthesis of many compounds of medical importance, including a large number of antibiotics. [1][2][3][4] Due to the modular structure of nonribosomal peptide synthetases (NRPSs) -comprising repeating domains performing specific catalytic functions -and their non-dependence on the ribosome, NRPS assembly lines are able to synthesise peptides from a wide range of amino acids. 1,3This feature, combined with the extensive incorporation of (D)-amino acids and large range of further structural modifications, contribute to the extensive diversity of natural NRPS-peptides. 1,2Given the complexity of many of these compounds that are of medical interest -such as the glycopeptide antibiotics ( Fig. 1), with vancomycin and teicoplanin as representative members -there is a need to characterise NRPS biosynthesis in order to explore the possibilities for compound development through redesigning the corresponding biosynthetic machinery. [1][2][3][4] In this regard, GPAs are perfect examples: total synthesis is highly challenging, meaning that all GPAs in clinical use stem from bacterial production in vivo and modified GPAs generated via total synthesis are not always accessible for the use in clinics. 4,5 The main reasons for this synthetic complexity are the high content of racemisation-prone phenylglycine residues as well as the highly crosslinked structure of GPAs (vancomycin:, which is formed by cytochrome P450 (Oxy) enzymes that interact with the unique NRPS domain found in GPA biosynthesis, the X-domain. 4,6,7 Fig. 1 GPA cyclisation in vitro is enabled by diastereomerically pure phenylglycine thioester peptides: teicoplanin seq. 5: R 1 = 4-Hpg; R 2 = Cl; R 3 = 3,5-Dpg; pekiskomycin seq. 6: R 1 = CH 3 ; R 2 = H; R 3 = Glu; actinoidin seq. 7: R 1 = 4-Hpg; R 2 = H; R 3 = Phe; vancomycin seq. 8: R 1 = Leu; R 2 = Cl; R 3 = Asn. PCP -peptidyl carrier protein domain, X -Oxy recruitment domain, A tei -OxyA from the teicoplanin system, B van -OxyB from the vancomycin system.

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confidence: 99%

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confidence: 99%

“…4,5 The main reasons for this synthetic complexity are the high content of racemisation-prone phenylglycine residues as well as the highly crosslinked structure of GPAs (vancomycin:…”

mentioning

confidence: 99%

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confidence: 99%

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A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis

et al. 2018

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“…lycopeptide antibiotics are an important class of natural products composed of glycosylated nonribosomal peptides produced by a diverse group of filamentous actinomycetes (1). Vancomycin, made by Amycolatopsis orientalis, and teicoplanin, produced by Actinoplanes teichomyceticus, are currently used for the treatment of life-threatening infections of pathogens, such as ␤-lactam-resistant Staphylococcus aureus, Enterococci spp., and Clostridium difficile (2)(3)(4).…”

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Relationship between Glycopeptide Production and Resistance in the Actinomycete Nonomuraea sp. ATCC 39727

Marcone

Binda

Carrano³

et al. 2014

Antimicrob Agents Chemother

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dGlycopeptides and ␤-lactams inhibit bacterial peptidoglycan synthesis in Gram-positive bacteria; resistance to these antibiotics is studied intensively in enterococci and staphylococci because of their relevance to infectious disease. Much less is known about antibiotic resistance in glycopeptide-producing actinomycetes that are likely to represent the evolutionary source of resistance determinants found in bacterial pathogens. Nonomuraea sp. ATCC 39727, the producer of A40926 (the precursor for the semisynthetic dalbavancin), does not harbor the canonical vanHAX genes. Consequently, we investigated the role of the ␤-lactamsensitive D,D-peptidase/D,D-carboxypeptidase encoded by vanY n , the only van-like gene found in the A40926 biosynthetic gene cluster, in conferring immunity to the antibiotic in Nonomuraea sp. ATCC 39727. Taking advantage of the tools developed recently to genetically manipulate this uncommon actinomycete, we varied vanY n gene dosage and expressed vanH at A at X at from the teicoplanin producer Actinoplanes teichomyceticus in Nonomuraea sp. ATCC 39727. Knocking out vanY n , complementing a vanY n mutant, or duplicating vanY n had no effect on growth but influenced antibiotic resistance and, in the cases of complementation and duplication, antibiotic production. Nonomuraea sp. ATCC 39727 was found to be resistant to penicillins, but its glycopeptide resistance was diminished in the presence of penicillin G, which inhibits VanY n activity. The heterologous expression of vanH at A at X at increased A40926 resistance in Nonomuraea sp. ATCC 39727 but did not increase antibiotic production, indicating that the level of antibiotic production is not directly determined by the level of resistance. The vanY n -based self-resistance in Nonomuraea sp. ATCC 39727 resembles the glycopeptide resistance mechanism described recently in mutants of Enterococcus faecium selected in vitro for high-level resistance to glycopeptides and penicillins.

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Chirality and Drug Discovery

Hagen

Helgren²

2021

Burger's Medicinal Chemistry and Drug Discovery

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The relationship between chirality and biological is extremely important to the pharmaceutical and biopharmaceutical areas as evidenced by the number of single enantiomer new drugs that have been developed and approved. This article covers several areas of importance for the design and synthesis of novel small molecules drugs to medicinal chemists. The chirality includes atropisomers and the impact of these chiral molecules and their biological implications are discussed. In addition to chirality at carbon, examples of chiral compounds involving chirality at non‐carbon atoms are included. A section titled “chiral switch” covers recent drug development and marketed of single enantiomers.

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Glycopeptide antibiotic biosynthesis

Cited by 167 publications

References 77 publications

A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis

A route to diastereomerically pure phenylglycine thioester peptides: crucial intermediates for investigating glycopeptide antibiotic biosynthesis

Relationship between Glycopeptide Production and Resistance in the Actinomycete Nonomuraea sp. ATCC 39727

Chirality and Drug Discovery

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