Synthesis and Study of Antibacterial Activities of Antibacterial Glycopeptide Antibiotics Conjugated with Benzoxaboroles

Printsevskaya, Svetlana S.; Reznikova, M. I.; Королев, А. М.; Lapa, G. B.; Olsufyeva, Eugenia N.; Preobrazhenskaya, M. N.; Plattner, Jacob J.; Zhang, Y K

doi:10.4155/fmc.13.16

Cited by 44 publications

(47 citation statements)

References 14 publications

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“…Semisynthetic derivatives 3–6 were synthesized from vancomycin (1) or eremomycin (2) by previously described methods 23 – 25 , 31 – 33 for glycopeptide carboxamides ( Figure 1 ). Compounds 3–6 were synthesized by condensation of 1 or 2 (1 eq.)…”

Section: Methodsmentioning

confidence: 99%

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties

Olsufyeva¹,

Shchekotikhin²,

Bychkova³

et al. 2018

DDDT

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PurposeDevelopment of new semisynthetic glycopeptides with improved antibacterial efficacy and reduced pseudoallergic reactions.MethodsSemisynthetic 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.ResultsThe 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 MIC90=0.5 mg/L, while vancomycin had MIC90=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).ConclusionThe 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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Section: Methodsmentioning

confidence: 99%

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties

Olsufyeva¹,

Shchekotikhin²,

Bychkova³

et al. 2018

DDDT

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“…94 The obtained conjugates proved to be Figure 20), with linkers between the glycopeptide and 6-aminobenzoxaborole fragments, were found to be active against vancomycin-resistant Enterococcus strains (MIC values in the range of 4−16 μg/mL, compared to >32 μg/mL for vancomycin, eremomycin, and teicoplanin aglycon). The study indicated that the spatial distance between glycopeptide and benzoxaborole may have an effect on the antibacterial activity of the conjugate.…”

Section: Medicinal Applicationsmentioning

confidence: 96%

Recent Developments in the Chemistry and Biological Applications of Benzoxaboroles

2015

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“…The Ramachandran group describes Focusing on boron in medicinal chemistry "Our focus has been on the inclusion of boron-containing molecules that can aid or stand alone in the treatment of diseases, rather than those important medicinal molecules whose production includes the application of organoborane chemistry" the synthesis of novel boronated a-methyl-gbutyrolactones as anti-cancer molecules [24] and the Preobrazhenskaya group has described the antibacterial activity of glycopeptide antibiotics conjugated with benzoxazaboroles [25].…”

Section: In This Issuementioning

confidence: 99%

Focusing on Boron in Medicinal Chemistry

Ramachandran

2013

Future Med. Chem.

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Synthesis and Study of Antibacterial Activities of Antibacterial Glycopeptide Antibiotics Conjugated with Benzoxaboroles

Abstract: Conjugation of antibiotics with benzoxaborole derivatives provides antibiotics with new and useful properties. Teicoplanin aglycone-benzoxaborole derivatives overcome resistance of Gram-positive bacteria to vancomycin.

Cited by 44 publications

References 14 publications

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties

Eremomycin pyrrolidide: a novel semisynthetic glycopeptide with improved chemotherapeutic properties

Recent Developments in the Chemistry and Biological Applications of Benzoxaboroles

Focusing on Boron in Medicinal Chemistry

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