New semisynthetic teicoplanin derivatives have comparable in vitro activity to that of oritavancin against clinical isolates of VRE

Szűcs, Zsolt; Ostorházi, Eszter; Kicsák, Máté; Nagy, Lajos; Borbás, Anikó; Herczegh, Pál

doi:10.1038/s41429-019-0164-1

Cited by 12 publications

(9 citation statements)

References 17 publications

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“…[15][16][17] In recent years, we conducted a systematic study on the synthesis of lipophilic derivatives of the glycopeptide antibiotics vancomycin, teicoplanin and ristocetin, and this yielded several new antibiotics with promising antibacterial and antiviral activity. [18][19][20][21][22] We demonstrated that the high lipophilicity of the side chains (C 8 À C 10 alkyl groups) in these molecules is essential for antiviral activity against, among others, influenza virus. However, antiviral activity proved accompanied by high cytotoxicity, probably due to a membrane-disrupting effect of the highly lipophilic side chains.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

et al. 2020

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The limited scope of antiviral drugs and increasing problem of antiviral drug resistance represent a global health threat. Glycopeptide antibiotics and their lipophilic derivatives have emerged as relevant inhibitors of diverse viruses. Herein, we describe a new strategy for the synthesis of dual hydrophobic and lipophobic derivatives of glycopeptides to produce selective antiviral agents without membrane‐disrupting activity. Perfluorobutyl and perfluorooctyl moieties were attached through linkers of different length to azido derivatives of vancomycin aglycone and teicoplanin pseudoaglycone, and the new derivatives were evaluated against a diverse panel of viruses. The teicoplanin derivatives displayed strong anti‐influenza virus activity at nontoxic concentrations. Some of the perfluoroalkylated glycopeptides were also active against a few other viruses such as herpes simplex virus or coronavirus. These data encourage further exploration of glycopeptide analogues for broad antiviral application.

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Section: Introductionmentioning

confidence: 99%

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

et al. 2020

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“…The primary mechanism of action of GPAs is the binding to the d-Ala-d-Ala terminus of peptidoglycan precursors of bacterial cell wall, thus blocking mature cell wall assembly and, ultimately, leading to cell lysis [22,23]. In novel derivatives, the incorporation of a new membrane depolarization and disruption mechanism improves efficacy and evades resistance [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

A Silkworm Infection Model for In Vivo Study of Glycopeptide Antibiotics

et al. 2020

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Glycopeptide antibiotics (GPAs) are drugs of last resort for treating infections by Gram-positive bacteria. They inhibit bacterial cell wall assembly by binding to the d-Ala-d-Ala terminus of peptidoglycan precursors, leading to cell lysis. Vancomycin and teicoplanin are first generation GPAs, while dalbavancin is one of the few, recently approved, second generation GPAs. In this paper, we developed an in vivo insect model to compare, for the first time, the efficacy of these three GPAs in curing Staphylococcus aureus infection. Differently from previous reports, Bombyx mori larvae were reared at 37 °C, and the course of infection was monitored, following not only larval survival, but also bacterial load in the insect body, hemocyte activity, phenoloxidase activity, and antimicrobial peptide expression. We demonstrated that the injection of S. aureus into the hemolymph of B. mori larvae led to a marked reduction of their survival rate within 24–48 h. GPAs were not toxic to the larvae and cured S. aureus infection. Dalbavancin was more effective than first generation GPAs. Due to its great advantages (i.e., easy and safe handling, low rearing costs, low antibiotic amount needed for the tests, no restrictions imposed by ethical and regulatory issues), this silkworm infection model could be introduced in preclinical phases—prior to the use of mice—accelerating the discovery/development rate of novel GPAs.

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“… 161 Optimization of 23 led to compound 24 , characterized by the addition of a basic moiety at the C-terminus, which displayed improved activity against VanA-type VRE (MIC = 0.15–2.5 μg/mL) while retaining potency against MRSA (MIC = 0.3 μg/mL) and VanB-type VRE (MIC = 0.15 μg/mL) ( Table 1 ). 162 In another attempt to confer anti-VanA-type VRE activity to teicoplanin-like compounds, analogue 25 , bearing an N-terminal guanidine moiety, was also synthesized. 163 This led to a vast improvement in potency toward vanA VRE isolates, with most strains tested showing susceptibility (MIC = 0.1–1.6 μg/mL) and with only a few strains exhibiting higher MIC values (6.25–12.5 μg/mL).…”

Section: Recent Developments In Semisynthetic Glycopeptide Antibioticsmentioning

confidence: 99%

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014–2022

2022

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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 Staphylococcus aureus (MRSA) and Streptococcus pneumoniae 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.

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New semisynthetic teicoplanin derivatives have comparable in vitro activity to that of oritavancin against clinical isolates of VRE

Cited by 12 publications

References 17 publications

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

Synthesis of Antiviral Perfluoroalkyl Derivatives of Teicoplanin and Vancomycin

A Silkworm Infection Model for In Vivo Study of Glycopeptide Antibiotics

Recent Advances in the Development of Semisynthetic Glycopeptide Antibiotics: 2014–2022

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