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Cold Spring Harbor Perspectives in... Dec 2016The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms... (Review)
Review
The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis. This is achieved primarily through binding to the d-alanyl-d-alanine terminus of the lipid II bacterial cell-wall precursor, preventing cross-linking of the peptidoglycan layer. Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillin-resistant Staphylococcus aureus and of susceptible Enterococcus spp. Newer lipoglycopeptide derivatives (telavancin, dalbavancin, and oritavancin) were designed in a targeted fashion to increase antibacterial activity, in some cases through secondary mechanisms of action. Resistance to the glycopeptides emerged in delayed fashion and occurs via a spectrum of chromosome- and plasmid-associated elements that lead to structural alteration of the bacterial cell-wall precursor substrates.
Topics: Anti-Bacterial Agents; Cell Wall; Drug Resistance, Bacterial; Glycopeptides; Methicillin-Resistant Staphylococcus aureus; Vancomycin-Resistant Enterococci
PubMed: 27663982
DOI: 10.1101/cshperspect.a026989 -
ACS Infectious Diseases Jan 2022Glycopeptides, a class of cell wall biosynthesis inhibitors, have been the antibiotics of choice against drug-resistant Gram-positive bacterial infections. Their unique... (Review)
Review
Glycopeptides, a class of cell wall biosynthesis inhibitors, have been the antibiotics of choice against drug-resistant Gram-positive bacterial infections. Their unique mechanism of action involving binding to the substrate of cell wall biosynthesis and substantial longevity in clinics makes this class of antibiotics an attractive choice for drug repurposing and reprofiling. However, resistance to glycopeptides has been observed due to alterations in the substrate, cell wall thickening, or both. The emergence of glycopeptide resistance has resulted in the development of synthetic and semisynthetic glycopeptide analogues to target acquired resistance. Recent findings demonstrate that these derivatives, along with some of the FDA approved glycopeptides have been shown to have antimicrobial activity against Gram-negative bacteria, Mycobacteria, and viruses thus expanding their spectrum of activity across the microbial kingdom. Additional mechanisms of action and identification of novel targets have proven to be critical in broadening the spectrum of activity of glycopeptides. This review focuses on the applications of glycopeptides beyond their traditional target group of Gram-positive bacteria. This will aid in making the scientific community aware about the nontraditional activity profiles of glycopeptides, identify the existing loopholes, and further explore this antibiotic class as a potential broad-spectrum antimicrobial agent.
Topics: Anti-Bacterial Agents; Glycopeptides; Gram-Negative Bacteria; Gram-Positive Bacteria; Gram-Positive Bacterial Infections; Humans
PubMed: 34878254
DOI: 10.1021/acsinfecdis.1c00367 -
Journal of Clinical Pharmacology Feb 1988Numerous glycopeptides continue to be described in the literature. They all share a similar heptapeptidic structure with a fixed spatial configuration that forms the... (Review)
Review
Numerous glycopeptides continue to be described in the literature. They all share a similar heptapeptidic structure with a fixed spatial configuration that forms the basis of their ability to recognize D-alanyl-D-alanine-containing structures in the cell wall. This complexation results in block of peptiglycan elongation; hence, inhibition of growth; and, eventually, cell death. The great variety of substituents on the heptapeptide forms the basis of a wide gradation of physico-chemical characteristics, namely net charge and lipophilicity, which, in turn, might explain the widely differing pharmacologic properties.
Topics: Anti-Bacterial Agents; Chemical Phenomena; Chemistry; Glycopeptides
PubMed: 3283178
DOI: 10.1002/j.1552-4604.1988.tb05737.x -
Expert Review of Proteomics May 2016Glycosylation is one of the most prominent and extensively studied protein post-translational modifications. However, traditional proteomic studies at the peptide level... (Review)
Review
Glycosylation is one of the most prominent and extensively studied protein post-translational modifications. However, traditional proteomic studies at the peptide level (bottom-up) rarely characterize intact glycopeptides (glycosylated peptides without removing glycans), so no glycoprotein heterogeneity information is retained. Intact glycopeptide characterization, on the other hand, provides opportunities to simultaneously elucidate the glycan structure and the glycosylation site needed to reveal the actual biological function of protein glycosylation. Recently, significant improvements have been made in the characterization of intact glycopeptides, ranging from enrichment and separation, mass spectroscopy (MS) detection, to bioinformatics analysis. In this review, we recapitulated currently available intact glycopeptide characterization methods with respect to their advantages and limitations as well as their potential applications.
Topics: Animals; Glycomics; Glycopeptides; Glycosylation; Humans; Mass Spectrometry; Proteomics
PubMed: 27140194
DOI: 10.1586/14789450.2016.1172965 -
The Journal of Antibiotics Sep 2014Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin... (Review)
Review
Glycopeptide antibiotics have been a key weapon in the fight against bacterial infections for over half a century, with the progenitors, vancomycin (1) and teicoplanin (2), still used extensively. The increased occurrence of resistance and the effectiveness of these 'last resort' treatments for Gram-positive infections has led to the discovery and clinical development of second generation, semisynthetic lipoglycopeptide derivatives such as telavancin (3), dalbavancin (4) and oritavancin (5), which all possess broader spectra of activity and improved pharmacokinetic properties. Two of these new antibiotics, telavancin (3) and dalbavancin (4), were approved in the past 5 years and the third, oritavancin (5), is awaiting regulatory approval. In this review, the discovery, development and associated resistance of vancomycin (1) and teicoplanin (2), and semi-synthetic glycopeptides, telavancin (3), dalbavancin (4) and oritavancin (5), are detailed. The clinical implications of glycopeptide resistance, especially vancomycin (1), as well as the future prospects for current glycopeptide drugs and the development of new glycopeptides are discussed.
Topics: Animals; Anti-Bacterial Agents; Drug Approval; Drug Design; Drug Resistance, Bacterial; Glycopeptides; Gram-Negative Bacteria; Gram-Positive Bacterial Infections; Humans
PubMed: 25118105
DOI: 10.1038/ja.2014.111 -
Chemical Society Reviews Jun 2013Synthetic glycopeptide dendrimers composed of a branched oligopeptide tree structure appended with glycosidic groups at its multiple N-termini were investigated for... (Review)
Review
Synthetic glycopeptide dendrimers composed of a branched oligopeptide tree structure appended with glycosidic groups at its multiple N-termini were investigated for binding to the Pseudomonas aeruginosa lectins LecB and LecA. These lectins are partly responsible for the formation of antibiotic resistant biofilms in the human pathogenic bacterium P. aeruginosa, which causes lethal airway infections in immune-compromised and cystic fibrosis patients. Glycopeptide dendrimers with high affinity to the lectins were identified by screening of combinatorial libraries. Several of these dendrimers, in particular the LecB specific glycopeptide dendrimers FD2 and D-FD2 and the LecA specific glycopeptide dendrimers GalAG2 and GalBG2, also efficiently block P. aeruginosa biofilm formation and induce biofilm dispersal in vitro. Structure-activity relationship and structural studies are reviewed, in particular the observation that multivalency is essential to the anti-biofilm effect in these dendrimers.
Topics: Anti-Bacterial Agents; Biofilms; Dendrimers; Glycopeptides; Lectins; Pseudomonas aeruginosa; Structure-Activity Relationship
PubMed: 23370573
DOI: 10.1039/c3cs35504g -
Methods in Enzymology 2022Glycopeptide antibiotics are essential drugs used to treat infections caused by multi-drug resistant Gram-positive pathogens. There is a continuous need for new...
Glycopeptide antibiotics are essential drugs used to treat infections caused by multi-drug resistant Gram-positive pathogens. There is a continuous need for new antibiotics, including GPAs, to address emerging resistance and offer desirable pharmacological profiles for improved efficacy. Microbial natural products are proven sources of antibiotics, and this source has dominated drug discovery over the past century. Bacteria from the phylum Actinobacteria are particularly renowned for producing a diverse range of bioactive natural products including glycopeptide antibiotics. The traditional approach to mining this resource is through the culture and extraction of natural products followed by assay for cell-killing activity. Unfortunately, this method no longer efficiently yields new antibiotic leads, delivering instead known compounds. Whole-genome sequencing programs on the other hand are revealing thousands of unexplored natural product biosynthetic gene clusters in the chromosomes of Actinobacteria. These gene clusters encode the necessary enzymes, transport and resistance mechanisms, along with regulatory elements for the biosynthesis of a variety of antibiotics. Identification of uncharacterized or cryptic biosynthetic gene clusters to unlock the chemical "dark matter" represents a new direction for the discovery of new drug candidates. This chapter discusses the identification of glycopeptide antibiotic biosynthetic gene clusters in microbial genomes, the improved production of these antibiotics using the GPAHex synthetic biology platform, and methods for their purification.
Topics: Anti-Bacterial Agents; Biological Products; Drug Discovery; Genomics; Glycopeptides
PubMed: 35379441
DOI: 10.1016/bs.mie.2021.11.009 -
ACS Infectious Diseases Aug 2022The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine's capacity to fight infectious diseases. Gram-positive species such... (Review)
Review
The accelerated appearance of drug-resistant bacteria poses an ever-growing threat to modern medicine's capacity to fight infectious diseases. Gram-positive species such as methicillin-resistant (MRSA) and continue to contribute significantly to the global burden of antimicrobial resistance. For decades, the treatment of serious Gram-positive infections relied upon the glycopeptide family of antibiotics, typified by vancomycin, as a last line of defense. With the emergence of vancomycin resistance, the semisynthetic glycopeptides telavancin, dalbavancin, and oritavancin were developed. The clinical use of these compounds is somewhat limited due to toxicity concerns and their unusual pharmacokinetics, highlighting the importance of developing next-generation semisynthetic glycopeptides with enhanced antibacterial activities and improved safety profiles. This Review provides an updated overview of recent advancements made in the development of novel semisynthetic glycopeptides, spanning the period from 2014 to today. A wide range of approaches are covered, encompassing innovative strategies that have delivered semisynthetic glycopeptides with potent activities against Gram-positive bacteria, including drug-resistant strains. We also address recent efforts aimed at developing targeted therapies and advances made in extending the activity of the glycopeptides toward Gram-negative organisms.
Topics: Anti-Bacterial Agents; Glycopeptides; Gram-Positive Bacteria; Methicillin-Resistant Staphylococcus aureus; Vancomycin
PubMed: 35895325
DOI: 10.1021/acsinfecdis.2c00253 -
Molecular & Cellular Proteomics : MCP Apr 2013Glycopeptide-based analysis is used to inform researchers about the glycans on one or more proteins. The method's key attractive feature is its ability to link... (Review)
Review
Glycopeptide-based analysis is used to inform researchers about the glycans on one or more proteins. The method's key attractive feature is its ability to link glycosylation information to exact locations (glycosylation sites) on proteins. Numerous applications for glycopeptide analysis are known, and several examples are described herein. The techniques used to characterize glycopeptides are still emerging, and recently, research focused on facilitating aspects of glycopeptide analysis has advanced significantly in the areas of sample preparation, MS fragmentation, and automation of data analysis. These recent developments, described herein, provide the foundation for the growth of glycopeptide analysis as a blossoming field.
Topics: Amino Acid Sequence; Animals; Carbohydrate Conformation; Carbohydrate Sequence; Glycopeptides; Glycosylation; Humans; Molecular Sequence Data; Peptide Fragments; Protein Processing, Post-Translational; Proteomics; Tandem Mass Spectrometry
PubMed: 23389047
DOI: 10.1074/mcp.R112.026567 -
Chembiochem : a European Journal of... Jan 2021The glycopeptide antibiotics (GPAs) are a fascinating example of complex natural product biosynthesis, with the nonribosomal synthesis of the peptide core coupled to a... (Review)
Review
The glycopeptide antibiotics (GPAs) are a fascinating example of complex natural product biosynthesis, with the nonribosomal synthesis of the peptide core coupled to a cytochrome P450-mediated cyclisation cascade that crosslinks aromatic side chains within this peptide. Given that the challenges associated with the synthesis of GPAs stems from their highly crosslinked structure, there is great interest in understanding how biosynthesis accomplishes this challenging set of transformations. In this regard, the use of in vitro experiments has delivered important insights into this process, including the identification of the unique role of the X-domain as a platform for P450 recruitment. In this minireview, we present an analysis of the results of in vitro studies into the GPA cyclisation cascade that have demonstrated both the tolerances and limitations of this process for modified substrates, and in turn developed rules for the future reengineering of this important antibiotic class.
Topics: Anti-Bacterial Agents; Cross-Linking Reagents; Glycopeptides; Molecular Conformation
PubMed: 32696500
DOI: 10.1002/cbic.202000309