Mannopeptimycins, a novel class of glycopeptide antibiotics active against gram-positive bacteria

He, Haiyin

doi:10.1007/s00253-004-1884-z

Cited by 28 publications

(11 citation statements)

References 34 publications

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“…AC98-6446 showed superior antimicrobial potency and properties, both in vitro and in vivo. 7,64 Laspartomycin is active against VRE and MRSA strains. Recently, enzymatic cleavage of its lipophilic moiety allowed the synthesis of various acylated derivatives (Figure 3b), even if none was more potent than the parent antibiotic.…”

Section: Chemical Derivativesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

223

126

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New antibiotics are necessary to treat microbial pathogens that are becoming increasingly resistant to available treatment. Despite the medical need, the number of newly approved drugs continues to decline. We offer an overview of the pipeline for new antibiotics at different stages, from compounds in clinical development to newly discovered chemical classes. Consistent with historical data, the majority of antibiotics under clinical development are natural products or derivatives thereof. However, many of them also represent improved variants of marketed compounds, with the consequent risk of being only partially effective against the prevailing resistance mechanisms. In the discovery arena, instead, compounds with promising activities have been obtained from microbial sources and from chemical modification of antibiotic classes other than those in clinical use. Furthermore, new natural product scaffolds have also been discovered by ingenious screening programs. After providing selected examples, we offer our view on the future of antibiotic discovery.

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Section: Chemical Derivativesmentioning

confidence: 99%

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Donadio¹,

Maffioli²,

Monciardini³

et al. 2010

J Antibiot

223

126

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“…Meeting this challenge requires the development of new antibiotics, preferably with modes of action that are distinct from those of current antimicrobial compounds. The mannopeptimycins are a group of five related cyclic glycopeptide antibiotics produced by Streptomyces hygroscopicus NRRL 30439 that are active against an array of Gram-positive pathogens (4–6). Of particular importance is the activity of the mannopeptimycins against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).…”

mentioning

confidence: 99%

Structural and Functional Characterization of MppR, an Enduracididine Biosynthetic Enzyme from Streptomyces hygroscopicus: Functional Diversity in the Acetoacetate Decarboxylase-like Superfamily

et al. 2013

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The non-proteinogenic amino acid enduracididine is a critical component of the mannopeptimycins, cyclic glycopeptide antibiotics with activity against drug-resistant pathogens including methicillin-resistant Staphylococcus aureus. Enduracididine is produced in Streptomyces hygroscopicus by three enzymes, MppP, MppQ, and MppR. Based on primary sequence analysis, MppP and Q are pyridoxal-5'-phosphate-dependent aminotransferases; MppR shares low, but significant, sequence identity with acetoacetate decarboxylase. The exact reactions catalyzed by each enzyme, and the intermediates involved in the route to enduracididine are currently unknown. Herein we present biochemical and structural characterization of MppR that demonstrates a catalytic activity for this enzyme and provides clues about its role in enduracididine biosynthesis. Bioinformatic analysis shows that MppR belongs to a previously uncharacterized family within the acetoacetate decarboxylase-like superfamily (ADCSF) and suggests that MppR-like enzymes may catalyze reactions diverging from the well-characterized, prototypical ADCSF decarboxylase activity. MppR shares a high degree of structural similarity with acetoacetate decarboxylase, though the respective quaternary structures differ markedly and structural differences in the active site explain the observed loss of decarboxylase activity. The crystal structure of MppR in the presence of a mixture of pyruvate and 4-imidazolecarboxaldehyde shows that MppR catalyzes the aldol condensation of these compounds and subsequent dehydration. Surprisingly, the structure of MppR in the presence of a mixture of "4-hydroxy-2-ketoarginine" and "2-ketoenduracididine" shows only the correct 4R-enantiomer of "2-ketoenduracididine" bound to the enzyme. These data, together with bioinformatic analysis of MppR homologs, identifies a novel family within the acetoacetate decarboxylase-like superfamily with divergent active site structure and, consequently, biochemical function.

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“…An array of ether [35–36], halogenated [36], acetal [37–39], benzoxazole [40], thiobenzoxazole [40], ester and carbonate [41] analogues were synthesised and evaluated for antibacterial activity. Only the semisynthetic derivatives possessing hydrophobic groups on the terminal sugar moiety (green) exhibited comparable antibacterial activity to the parent compound and reference antibiotics [42]. …”

Section: Reviewmentioning

confidence: 99%

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

Atkinson¹,

Naysmith²,

Furkert³

et al. 2016

Beilstein J. Org. Chem.

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Rising resistance to current clinical antibacterial agents is an imminent threat to global public health and highlights the demand for new lead compounds for drug discovery. One such potential lead compound, the peptide antibiotic teixobactin, was recently isolated from an uncultured bacterial source, and demonstrates remarkably high potency against a wide range of resistant pathogens without apparent development of resistance. A rare amino acid residue component of teixobactin, enduracididine, is only known to occur in a small number of natural products that also possess promising antibiotic activity. This review highlights the presence of enduracididine in natural products, its biosynthesis together with a review of analogues of enduracididine. Reported synthetic approaches to the cyclic guanidine structure of enduracididine are discussed, illustrating the challenges encountered to date in the development of efficient synthetic routes to facilitate drug discovery efforts inspired by the discovery of teixobactin.

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Mannopeptimycins, a novel class of glycopeptide antibiotics active against gram-positive bacteria

Cited by 28 publications

References 34 publications

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Antibiotic discovery in the twenty-first century: current trends and future perspectives

Structural and Functional Characterization of MppR, an Enduracididine Biosynthetic Enzyme from Streptomyces hygroscopicus: Functional Diversity in the Acetoacetate Decarboxylase-like Superfamily

Enduracididine, a rare amino acid component of peptide antibiotics: Natural products and synthesis

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