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Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties

PURPOSE: Development of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions. METHODS: Semisynthetic glycopeptides 3–6 were synthesized from vancomycin (1) or eremomycin (2) by the condensation with pyrrolidine or piperidine. The minimum inhibitor...

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Autores principales: Olsufyeva, Evgenia N, Shchekotikhin, Andrey E, Bychkova, Elena N, Pereverzeva, Eleonora R, Treshalin, Ivan D, Mirchink, Elena P, Isakova, Elena B, Chernobrovkin, Mikhail G, Kozlov, Roman S, Dekhnich, Andrey V, Preobrazhenskaya, Maria N
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dove Medical Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137948/
https://www.ncbi.nlm.nih.gov/pubmed/30237697
http://dx.doi.org/10.2147/DDDT.S173923
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author Olsufyeva, Evgenia N
Shchekotikhin, Andrey E
Bychkova, Elena N
Pereverzeva, Eleonora R
Treshalin, Ivan D
Mirchink, Elena P
Isakova, Elena B
Chernobrovkin, Mikhail G
Kozlov, Roman S
Dekhnich, Andrey V
Preobrazhenskaya, Maria N
author_facet Olsufyeva, Evgenia N
Shchekotikhin, Andrey E
Bychkova, Elena N
Pereverzeva, Eleonora R
Treshalin, Ivan D
Mirchink, Elena P
Isakova, Elena B
Chernobrovkin, Mikhail G
Kozlov, Roman S
Dekhnich, Andrey V
Preobrazhenskaya, Maria N
author_sort Olsufyeva, Evgenia N
collection PubMed
description PURPOSE: Development of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions. METHODS: Semisynthetic glycopeptides 3–6 were synthesized from vancomycin (1) or eremomycin (2) by the condensation with pyrrolidine or piperidine. The minimum inhibitory concentration (MIC) for the new derivatives was measured by the broth micro-dilution method on a panel of clinical isolates of Staphylococcus and Enterococcus. Acute toxicity (50% lethal dose, maximum tolerated doses), antibacterial efficacy on model of systemic bacterial infection with S. aureus and pseudoallergic inflammatory reaction (on concanavalin A) of eremomycin pyrrolidide (5) were evaluated in mice according to standard procedures. RESULTS: The eremomycin pyrrolidide (5) was the most active compound and showed a high activity against Gram-positive bacteria: vancomycin-susceptible staphylococci and enterococci (minimum inhibitory concentrations [MICs] 0.13–0.25 mg/L), as well as vancomycin-intermediate resistant Staphylococcus aureus (MICs 1 mg/L). Antimicrobial susceptibility tested on a panel of 676 isolates showed that 5 had similar activity for the genera Staphylococcus and Enterococcus with MIC(90)=0.5 mg/L, while vancomycin had MIC(90)=1–2 mg/L. The number of resistant strains of Enterococcus faecium (vancomycin-resistant enterococci) (MIC =64 mg/L) with this value was 7 (8%) for vancomycin (1) and 0 for the compound 5. In vivo comparative studies in a mouse model of systemic bacterial infection with S. aureus demonstrated that the efficacy of 5 was notably higher than that of the original antibiotics 1 and 2. In contrast to 1, compound 5 did not induce pseudoallergic inflammatory reaction (on concanavalin A). CONCLUSION: The new semisynthetic derivative eremomycin pyrrolidide (5) has high activity against staphylococci and enterococci including vancomycin-resistant strains. Compound 5 has a higher efficacy in a model of staphylococcal sepsis than vancomycin (1) or eremomycin (2). In striking contrast to natural antibiotics, the novel derivative 5 does not induce a pseudoallergic inflammatory reaction to concanavalin A and therefore has no histamine release activity. These results indicate the advantages of a new semisynthetic glycopeptide antibiotic eremomycin pyrrolidide (5) which may be a prospective antimicrobial agent for further pre-clinical and clinical evaluations.
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spelling pubmed-61379482018-09-20 Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties Olsufyeva, Evgenia N Shchekotikhin, Andrey E Bychkova, Elena N Pereverzeva, Eleonora R Treshalin, Ivan D Mirchink, Elena P Isakova, Elena B Chernobrovkin, Mikhail G Kozlov, Roman S Dekhnich, Andrey V Preobrazhenskaya, Maria N Drug Des Devel Ther Original Research PURPOSE: Development of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions. METHODS: Semisynthetic glycopeptides 3–6 were synthesized from vancomycin (1) or eremomycin (2) by the condensation with pyrrolidine or piperidine. The minimum inhibitory concentration (MIC) for the new derivatives was measured by the broth micro-dilution method on a panel of clinical isolates of Staphylococcus and Enterococcus. Acute toxicity (50% lethal dose, maximum tolerated doses), antibacterial efficacy on model of systemic bacterial infection with S. aureus and pseudoallergic inflammatory reaction (on concanavalin A) of eremomycin pyrrolidide (5) were evaluated in mice according to standard procedures. RESULTS: The eremomycin pyrrolidide (5) was the most active compound and showed a high activity against Gram-positive bacteria: vancomycin-susceptible staphylococci and enterococci (minimum inhibitory concentrations [MICs] 0.13–0.25 mg/L), as well as vancomycin-intermediate resistant Staphylococcus aureus (MICs 1 mg/L). Antimicrobial susceptibility tested on a panel of 676 isolates showed that 5 had similar activity for the genera Staphylococcus and Enterococcus with MIC(90)=0.5 mg/L, while vancomycin had MIC(90)=1–2 mg/L. The number of resistant strains of Enterococcus faecium (vancomycin-resistant enterococci) (MIC =64 mg/L) with this value was 7 (8%) for vancomycin (1) and 0 for the compound 5. In vivo comparative studies in a mouse model of systemic bacterial infection with S. aureus demonstrated that the efficacy of 5 was notably higher than that of the original antibiotics 1 and 2. In contrast to 1, compound 5 did not induce pseudoallergic inflammatory reaction (on concanavalin A). CONCLUSION: The new semisynthetic derivative eremomycin pyrrolidide (5) has high activity against staphylococci and enterococci including vancomycin-resistant strains. Compound 5 has a higher efficacy in a model of staphylococcal sepsis than vancomycin (1) or eremomycin (2). In striking contrast to natural antibiotics, the novel derivative 5 does not induce a pseudoallergic inflammatory reaction to concanavalin A and therefore has no histamine release activity. These results indicate the advantages of a new semisynthetic glycopeptide antibiotic eremomycin pyrrolidide (5) which may be a prospective antimicrobial agent for further pre-clinical and clinical evaluations. Dove Medical Press 2018-09-10 /pmc/articles/PMC6137948/ /pubmed/30237697 http://dx.doi.org/10.2147/DDDT.S173923 Text en © 2018 Olsufyeva et al. This work is published and licensed by Dove Medical Press Limited The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
spellingShingle Original Research
Olsufyeva, Evgenia N
Shchekotikhin, Andrey E
Bychkova, Elena N
Pereverzeva, Eleonora R
Treshalin, Ivan D
Mirchink, Elena P
Isakova, Elena B
Chernobrovkin, Mikhail G
Kozlov, Roman S
Dekhnich, Andrey V
Preobrazhenskaya, Maria N
Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties
title Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties
title_full Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties
title_fullStr Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties
title_full_unstemmed Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties
title_short Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties
title_sort eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137948/
https://www.ncbi.nlm.nih.gov/pubmed/30237697
http://dx.doi.org/10.2147/DDDT.S173923
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