Glycopeptide Antibiotics 2021

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 35369

Special Issue Editor


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Guest Editor
Department of Pharmaceutical Chemistry, University of Debrecen, Debrecen, Hungary
Interests: glycopeptides; antibiotics; synthesis; antibacterial activity; mechanism of action; antibiotic resistance

Special Issue Information

Dear Colleagues,

As Guest Editor, I kindly invite you to submit a manuscript to the Special Issue “Glycopeptide Antibiotics”, which will be published in Pharmaceuticals. The Special Issue focuses on all topics related to glycopeptide antibiotics: the (semi)synthetic modification of glycopeptides; investigation of the mechanism of action; antibiotic resistance related topics; studies on antibacterial or antimicrobial activity of glycopeptides; structure determination and spectroscopic issues.

We sincerely hope that you or a member of your laboratory will be able to contribute.

Dr. Magdolna Csávás
Guest Editor

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Keywords

  • glycopeptides
  • antibiotics
  • synthesis
  • antibacterial activity
  • mechanism of action
  • antibiotic resistance

Published Papers (10 papers)

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Research

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14 pages, 5923 KiB  
Article
Impact of Linker Modification and PEGylation of Vancomycin Conjugates on Structure-Activity Relationships and Pharmacokinetics
by Florian Umstätter, Julia Werner, Leah Zerlin, Eric Mühlberg, Christian Kleist, Karel D. Klika, Tobias Hertlein, Barbro Beijer, Cornelius Domhan, Stefan Zimmermann, Knut Ohlsen, Uwe Haberkorn, Walter Mier and Philipp Uhl
Pharmaceuticals 2022, 15(2), 159; https://doi.org/10.3390/ph15020159 - 28 Jan 2022
Cited by 2 | Viewed by 3464
Abstract
As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant [...] Read more.
As multidrug-resistant bacteria represent a concerning burden, experts insist on the need for a dramatic rethinking on antibiotic use and development in order to avoid a post-antibiotic era. New and rapidly developable strategies for antimicrobial substances, in particular substances highly potent against multidrug-resistant bacteria, are urgently required. Some of the treatment options currently available for multidrug-resistant bacteria are considerably limited by side effects and unfavorable pharmacokinetics. The glycopeptide vancomycin is considered an antibiotic of last resort. Its use is challenged by bacterial strains exhibiting various types of resistance. Therefore, in this study, highly active polycationic peptide-vancomycin conjugates with varying linker characteristics or the addition of PEG moieties were synthesized to optimize pharmacokinetics while retaining or even increasing antimicrobial activity in comparison to vancomycin. The antimicrobial activity of the novel conjugates was determined by microdilution assays on susceptible and vancomycin-resistant bacterial strains. VAN1 and VAN2, the most promising linker-modified derivatives, were further characterized in vivo with molecular imaging and biodistribution studies in rodents, showing that the linker moiety influences both antimicrobial activity and pharmacokinetics. Encouragingly, VAN2 was able to undercut the resistance breakpoint in microdilution assays on vanB and vanC vancomycin-resistant enterococci. Out of all PEGylated derivatives, VAN:PEG1 and VAN:PEG3 were able to overcome vanC resistance. Biodistribution studies of the novel derivatives revealed significant changes in pharmacokinetics when compared with vancomycin. In conclusion, linker modification of vancomycin-polycationic peptide conjugates represents a promising strategy for the modulation of pharmacokinetic behavior while providing potent antimicrobial activity. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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16 pages, 2318 KiB  
Article
The First Dimeric Derivatives of the Glycopeptide Antibiotic Teicoplanin
by Ilona Bereczki, Zsolt Szűcs, Gyula Batta, Tamás Milán Nagy, Eszter Ostorházi, Katalin E. Kövér, Anikó Borbás and Pál Herczegh
Pharmaceuticals 2022, 15(1), 77; https://doi.org/10.3390/ph15010077 - 8 Jan 2022
Cited by 4 | Viewed by 1944
Abstract
Various dimeric derivatives of the glycopeptide antibiotic teicoplanin were prepared with the aim of increasing the activity of the parent compound against glycopeptide-resistant bacteria, primarily vancomycin-resistant enterococci. Starting from teicoplanin, four covalent dimers were prepared in two orientations, using an α,ω-bis-isothiocyanate linker. Formation [...] Read more.
Various dimeric derivatives of the glycopeptide antibiotic teicoplanin were prepared with the aim of increasing the activity of the parent compound against glycopeptide-resistant bacteria, primarily vancomycin-resistant enterococci. Starting from teicoplanin, four covalent dimers were prepared in two orientations, using an α,ω-bis-isothiocyanate linker. Formation of a dimeric cobalt coordination complex of an N-terminal L-histidyl derivative of teicoplanin pseudoaglycone has been detected and its antibacterial activity evaluated. The Co(III)-induced dimerization of the histidyl derivative was demonstrated by DOSY experiments. Both the covalent and the complex dimeric derivatives showed high activity against VanA teicoplanin-resistant enterococci, but their activity against other tested bacterial strains did not exceed that of the monomeric compounds. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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12 pages, 2932 KiB  
Article
Two Novel Semisynthetic Lipoglycopeptides Active against Staphylococcus aureus Biofilms and Cells in Late Stationary Growth Phase
by Vladimir Vimberg, Leona Zieglerova, Aninda Mazumdar, Zsolt Szűcs, Aniko Borbás, Pál Herczegh and Gabriela Balikova Novotna
Pharmaceuticals 2021, 14(11), 1182; https://doi.org/10.3390/ph14111182 - 19 Nov 2021
Viewed by 2105
Abstract
The increase in antibiotic resistance among Gram-positive bacteria underscores the urgent need to develop new antibiotics. New antibiotics should target actively growing susceptible bacteria that are resistant to clinically accepted antibiotics including bacteria that are not growing or are protected in a biofilm [...] Read more.
The increase in antibiotic resistance among Gram-positive bacteria underscores the urgent need to develop new antibiotics. New antibiotics should target actively growing susceptible bacteria that are resistant to clinically accepted antibiotics including bacteria that are not growing or are protected in a biofilm environment. In this paper, we compare the in vitro activities of two new semisynthetic glycopeptide antibiotics, MA79 and ERJ390, with two clinically used glycopeptide antibiotics—vancomycin and teicoplanin. The new antibiotics effectively killed not only exponentially growing cells of Staphylococcus aureus, but also cells in the stationary growth phase and biofilm. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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25 pages, 2523 KiB  
Article
Natural Apocarotenoids and Their Synthetic Glycopeptide Conjugates Inhibit SARS-CoV-2 Replication
by Ilona Bereczki, Henrietta Papp, Anett Kuczmog, Mónika Madai, Veronika Nagy, Attila Agócs, Gyula Batta, Márton Milánkovits, Eszter Ostorházi, Ana Mitrović, Janko Kos, Áron Zsigmond, István Hajdú, Zsolt Lőrincz, Dávid Bajusz, György Miklós Keserű, Jan Hodek, Jan Weber, Ferenc Jakab, Pál Herczegh and Anikó Borbásadd Show full author list remove Hide full author list
Pharmaceuticals 2021, 14(11), 1111; https://doi.org/10.3390/ph14111111 - 30 Oct 2021
Cited by 8 | Viewed by 4143
Abstract
The protracted global COVID-19 pandemic urges the development of new drugs against the causative agent SARS-CoV-2. The clinically used glycopeptide antibiotic, teicoplanin, emerged as a potential antiviral, and its efficacy was improved with lipophilic modifications. This prompted us to prepare new lipophilic apocarotenoid [...] Read more.
The protracted global COVID-19 pandemic urges the development of new drugs against the causative agent SARS-CoV-2. The clinically used glycopeptide antibiotic, teicoplanin, emerged as a potential antiviral, and its efficacy was improved with lipophilic modifications. This prompted us to prepare new lipophilic apocarotenoid conjugates of teicoplanin, its pseudoaglycone and the related ristocetin aglycone. Their antiviral effect was tested against SARS-CoV-2 in Vero E6 cells, using a cell viability assay and quantitative PCR of the viral RNA, confirming their micromolar inhibitory activity against viral replication. Interestingly, two of the parent apocarotenoids, bixin and β-apo-8′carotenoic acid, exerted remarkable anti-SARS-CoV-2 activity. Mechanistic studies involved cathepsin L and B, as well as the main protease 3CLPro, and the results were rationalized by computational studies. Glycopeptide conjugates show dual inhibitory action, while apocarotenoids have mostly cathepsin B and L affinity. Since teicoplanin is a marketed antibiotic and the natural bixin is an approved, cheap and widely used red colorant food additive, these readily available compounds and their conjugates as potential antivirals are worthy of further exploration. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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7 pages, 716 KiB  
Article
Impact of Clostridioides difficile Therapy on Nosocomial Acquisition of Vancomycin-Resistant Enterococci
by Carlos L. Correa-Martínez, Niklas C. J. Hagemeier, Neele J. Froböse and Stefanie Kampmeier
Pharmaceuticals 2021, 14(11), 1066; https://doi.org/10.3390/ph14111066 - 21 Oct 2021
Cited by 5 | Viewed by 2310
Abstract
Vancomycin is frequently used for the treatment of C. difficile infections (CDI). There are concerns that this might increase the risk of selecting vancomycin resistant enterococci (VRE). Here, we evaluated whether there is an increased risk of VRE acquisition following vancomycin for CDI [...] Read more.
Vancomycin is frequently used for the treatment of C. difficile infections (CDI). There are concerns that this might increase the risk of selecting vancomycin resistant enterococci (VRE). Here, we evaluated whether there is an increased risk of VRE acquisition following vancomycin for CDI specific treatment. Patients with CDI, metronidazole, or oral vancomycin treatment and without preexisting VRE were monitored for VRE acquisition. VRE isolates from patients with acquired and preexisting colonization were collected and subjected to whole genome sequencing. In total, 281 patients (median age 56 years, 54% of the male sex) presented with toxin positive C. difficile. Of them, 170 patients met the inclusion criteria, comprising 37 patients treated with metronidazole and 133 treated with oral vancomycin. In total, 14 patients meeting the inclusion criteria acquired VRE (vancomycin: n = 11; metronidazole: n = 3). Statistical analysis revealed no significant differences between both VRE acquisition rates. Genetic comparison of detected VRE isolates resulted in eight clusters of closely related genotypes comprising acquired and preexisting strains. Our results suggest that vancomycin and metronidazole likewise increase the risk of VRE acquisition. Genetic comparison indicates that VRE acquisition is a result of both antibiotic selection and pathogen transmission. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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12 pages, 1240 KiB  
Article
Aminoalkylamides of Eremomycin Exhibit an Improved Antibacterial Activity
by Elena I. Moiseenko, Réka Erdei, Natalia E. Grammatikova, Elena P. Mirchink, Elena B. Isakova, Eleonora R. Pereverzeva, Gyula Batta and Andrey E. Shchekotikhin
Pharmaceuticals 2021, 14(4), 379; https://doi.org/10.3390/ph14040379 - 19 Apr 2021
Cited by 4 | Viewed by 2119
Abstract
After decades, the glycopeptide vancomycin is still the preferred antibiotic against resistant strains of Gram-positive bacteria. Although its clinical use is strictly regulated, the gradual spread of vancomycin-resistant bacteria, such as glycopeptide-resistant and glycopeptide-intermediate Staphylococcus aureus and vancomycin-resistant Enterococcus spp., is a serious [...] Read more.
After decades, the glycopeptide vancomycin is still the preferred antibiotic against resistant strains of Gram-positive bacteria. Although its clinical use is strictly regulated, the gradual spread of vancomycin-resistant bacteria, such as glycopeptide-resistant and glycopeptide-intermediate Staphylococcus aureus and vancomycin-resistant Enterococcus spp., is a serious health problem. Based on the literature data and previous studies, our main goal was to assess the antimicrobial potential and to study the structure–activity relationship of new eremomycin aminoalkylamides. We designed and synthesized a series of new eremomycin amides in which eremomycin is conjugated with a hydrophobic arylalkyl group via an alkylenediamine spacer, and tested their antibacterial activities on a panel of Gram-positive strains that were sensitive and resistant to a “gold-standard” vancomycin. Based on the data obtained, the structure–activity relationships were investigated, and a lead compound was selected for in-depth testing. Research carried out using an in vivo model of staphylococcus sepsis, acute toxicity studies, and the estimated therapeutic index also showed the advantage of the selected eremomycin amide derivative in particular, as well as the chosen direction in general. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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14 pages, 3430 KiB  
Article
Bacterial Cell Wall Analogue Peptides Control the Oligomeric States and Activity of the Glycopeptide Antibiotic Eremomycin: Solution NMR and Antimicrobial Studies
by László Izsépi, Réka Erdei, Anna N. Tevyashova, Natalia E. Grammatikova, Andrey E. Shchekotikhin, Pál Herczegh and Gyula Batta
Pharmaceuticals 2021, 14(2), 83; https://doi.org/10.3390/ph14020083 - 22 Jan 2021
Cited by 4 | Viewed by 2177
Abstract
For some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant Staphylococcus aureus (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of glycopeptide antibiotics is essentially the binding of [...] Read more.
For some time, glycopeptide antibiotics have been considered the last line of defense against Methicillin-resistant Staphylococcus aureus (MRSA). However, vancomycin resistance of Gram-positive bacteria is an increasingly emerging worldwide health problem. The mode of action of glycopeptide antibiotics is essentially the binding of peptidoglycan cell-wall fragments terminating in the d-Ala-d-Ala sequence to the carboxylate anion binding pocket of the antibiotic. Dimerization of these antibiotics in aqueous solution was shown to persist and even to enhance the antibacterial effect in a co-operative manner. Some works based on solid state (ss) Nuclear Magnetic Resonance (NMR) studies questioned the presence of dimers under the conditions of ssNMR while in a few cases, higher-order oligomers associated with contiguous back-to-back and face-to-face dimers were observed in the crystal phase. However, it is not proved if such oligomers persist in aqueous solutions. With the aid of 15N-labelled eremomycin using 15N relaxation and diffusion NMR methods, we observed tetramers and octamers when the N-Ac-d-Ala-d-Ala dipeptide was added. To the contrary, the N-Ac-d-Ala or (N-Ac)2-l-Lys-d-Ala-d-Ala tripeptide did not induce higher-order oligomers. These observations are interesting examples of tailored supramolecular self-organization. New antimicrobial tests have also been carried out with these self-assemblies against MRSA and VRE (resistant) strains. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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15 pages, 1582 KiB  
Article
Reprogramming of the Antibacterial Drug Vancomycin Results in Potent Antiviral Agents Devoid of Antibacterial Activity
by Zsolt Szűcs, Lieve Naesens, Annelies Stevaert, Eszter Ostorházi, Gyula Batta, Pál Herczegh and Anikó Borbás
Pharmaceuticals 2020, 13(7), 139; https://doi.org/10.3390/ph13070139 - 29 Jun 2020
Cited by 16 | Viewed by 4391
Abstract
Influenza A and B viruses are a global threat to human health and increasing resistance to the existing antiviral drugs necessitates new concepts to expand the therapeutic options. Glycopeptide derivatives have emerged as a promising new class of antiviral agents. To avoid potential [...] Read more.
Influenza A and B viruses are a global threat to human health and increasing resistance to the existing antiviral drugs necessitates new concepts to expand the therapeutic options. Glycopeptide derivatives have emerged as a promising new class of antiviral agents. To avoid potential antibiotic resistance, these antiviral glycopeptides are preferably devoid of antibiotic activity. We prepared six vancomycin aglycone hexapeptide derivatives with the aim of obtaining compounds having anti-influenza virus but no antibacterial activity. Two of them exerted strong and selective inhibition of influenza A and B virus replication, while antibacterial activity was successfully eliminated by removing the critical N-terminal moiety. In addition, these two molecules offered protection against several other viruses, such as herpes simplex virus, yellow fever virus, Zika virus, and human coronavirus, classifying these glycopeptides as broad antiviral molecules with a favorable therapeutic index. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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14 pages, 1932 KiB  
Article
Vancomycin-Lipopeptide Conjugates with High Antimicrobial Activity on Vancomycin-Resistant Enterococci
by Eric Mühlberg, Florian Umstätter, Cornelius Domhan, Tobias Hertlein, Knut Ohlsen, Andreas Krause, Christian Kleist, Barbro Beijer, Stefan Zimmermann, Uwe Haberkorn, Walter Mier and Philipp Uhl
Pharmaceuticals 2020, 13(6), 110; https://doi.org/10.3390/ph13060110 - 29 May 2020
Cited by 16 | Viewed by 6789
Abstract
Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria [...] Read more.
Multidrug-resistant bacteria represent one of the most important health care problems worldwide. While there are numerous drugs available for standard therapy, there are only a few compounds capable of serving as a last resort for severe infections. Therefore, approaches to control multidrug-resistant bacteria must be implemented. Here, a strategy of reactivating the established glycopeptide antibiotic vancomycin by structural modification with polycationic peptides and subsequent fatty acid conjugation to overcome the resistance of multidrug-resistant bacteria was followed. This study especially focuses on the structure–activity relationship, depending on the modification site and fatty acid chain length. The synthesized conjugates showed high antimicrobial potential on vancomycin-resistant enterococci. We were able to demonstrate that the antimicrobial activity of the vancomycin-lipopeptide conjugates depends on the chain length of the attached fatty acid. All conjugates showed good cytocompatibility in vitro and in vivo. Radiolabeling enabled the in vivo determination of pharmacokinetics in Wistar rats by molecular imaging and biodistribution studies. An improved biodistribution profile in comparison to unmodified vancomycin was observed. While vancomycin is rapidly excreted by the kidneys, the most potent conjugate shows a hepatobiliary excretion profile. In conclusion, these results demonstrate the potential of the structural modification of already established antibiotics to provide highly active compounds for tackling multidrug-resistant bacteria. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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Review

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12 pages, 2281 KiB  
Review
Teicoplanin—A New Use for an Old Drug in the COVID-19 Era?
by Vladimir Vimberg
Pharmaceuticals 2021, 14(12), 1227; https://doi.org/10.3390/ph14121227 - 26 Nov 2021
Cited by 11 | Viewed by 4296
Abstract
Teicoplanin is an antibiotic that has been actively used in medical practice since 1986 to treat serious Gram-positive bacterial infections. Due to its efficiency and low cytotoxicity, teicoplanin has also been used for patients with complications, including pediatric and immunocompromised patients. Although teicoplanin [...] Read more.
Teicoplanin is an antibiotic that has been actively used in medical practice since 1986 to treat serious Gram-positive bacterial infections. Due to its efficiency and low cytotoxicity, teicoplanin has also been used for patients with complications, including pediatric and immunocompromised patients. Although teicoplanin is accepted as an antibacterial drug, its action against RNA viruses, including SARS-CoV2, has been proven in vitro. Here, we provide a thorough overview of teicoplanin usage in medicine, based on the current literature. We summarize infection sites treated with teicoplanin, concentrations of the antibiotic in different organs, and side effects. Finally, we summarize all available data about the antiviral activity of teicoplanin. We believe that, due to the extensive experience of teicoplanin usage in clinical settings to treat bacterial infections and its demonstrated activity against SARS-CoV2, teicoplanin could become a drug of choice in the treatment of COVID-19 patients. Teicoplanin stops the replication of the virus and at the same time avoids the development of Gram-positive bacterial co-infections. Full article
(This article belongs to the Special Issue Glycopeptide Antibiotics 2021)
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