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Kang and Park: Glycopeptide Antibiotics: Structure and Mechanisms of Action
Review Article

J Bacteriol Virol 2015;45(2):67-78.

Published online: 9 February 2015

DOI: https://doi.org/10.4167/jbv.2015.45.2.67

Glycopeptide Antibiotics: Structure and Mechanisms of Action

Hee-Kyoung Kang1, Yoonkyung Park1, 2, ∗

1Department of Biomedical Sciences, Chosun University, Gwangju, Korea

2Research Center for Proteinaceous Materials, Chosun University, Gwangju, Korea

∗Corresponding author: Yoonkyung Park. Department of Biomedical Sciences and Research Center for Proteinaceous Materials, Chosun University, Gwangju 501-759, Korea. Phone: +82-62-230-6854, Fax: +82-62-225-6758, e-mail: y_k_park@chosun.ac.kr

∗∗ This work was supported by grants from the National Research Foundation of Korea (NRF) funded by the Korean Government (MEST; No. 2011-0017532) and the Global Research Laboratory (GRL; NRF-2014K1A1A2064460).

Received 7 April 201518 April 2015       Accepted 20 April 2015

Copyright © 2015 Journal of Bacteriology and Virology

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Glycopeptides of the clinically important antibiotic drugs are glycosylated cyclic or polycyclic nonribosomal peptides. Glycopeptides such as vancomycin and teicoplanin are often used for the treatment of gram-positive bacteria in patients. The increased incidence of drug resistance and inadequacy of these therapeutics against gram-positive bacterial infections would be the formation and clinical development of more variable second generation of glycopeptide antibiotics: semisynthetic lipoglycopeptide analogs such as telavancin, dalbavancin, and oritavancin with improved activity and better pharmacokinetic properties. In this review, we describe the development of and bacterial resistance to vancomycin, teicoplanin, and semisynthetic glycopeptides (teicoplanin, dalbavancin, and oritavancin). The clinical influence of resistance to glycopeptides, particularly vancomycin, are also discussed.

Keywords: Glycopeptide, Resistance, Vancomycin, Teicoplanin, Dalbavancin

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Figure 1.
The chemical structure of glycopeptides. Vancomycin and teicoplanin are natural products. In teicoplanin, A2-1 through A2-5 denote the components of the complex that are characterized by a fatty-acid moiety at position R. Oritavancin and telavancin are semisynthetic second-generation glycopeptides from the vancomycin family. Dalbavancin is a semisynthetic derivative of teicoplanin.
jbv-45-67f1.tif
Figure 2.
Alignment of van resistance gene clusters from glycopeptide antibiotics-producing bacteria. Arrows indicate the direction of transcription. Empty arrow indicate hypothetical gene. A to N represent the D-Ala-D-Lac ligase giving name to the gene cluster. U, transcription regulator; R, regulator; S, histidine kinase; H, dehydrogenase; Y, D,D-carboxypeptidase; W and Z, unknown protein; vanXY, D,D-carboxypeptidase/D,D-dipeptidase; T, serine recemase.
jbv-45-67f2.tif
Table 1.
Types of resistance to vancomycin and teicoplanin among enterococci, in relation to alternative peptidoglycans
Glycopeptide -resistant phenotype Microorganism Resistance level MIC (mg/mL) Location of van genes Transcription of genes C-terminus of modified target Reference
Vancomycin Teicoplanin
VanA E. faecalis E. faecium High 64~100 16~512 Plasmid Chromosome Inducible D-Ala-D-Lac 32~34
VanB E. faecalis E. faecium Variable 4~1,000 0.5~1.0 Plasmid Chromosome Inducible D-Ala-D-Lac 34~36
VanC E. gallinarum E. casseliflavus E. flavescens Low intrinsic level 2~32 0.5~1.0 Chromosome Constitutive D-Ala-D-D-Ser 35, 36, 43
VanD E. faecalis E. faecium Moderate 64~128 6~64 Chromosome Constitutive D-Ala-D-Lac 35, 37
VanE E. faecalis Low 8~32 0.5 Chromosome Inducible D-Ala-D-Ser 35
VanG E. faecalis E. faecium Low 16 0.5 Chromosome Inducible D-Ala-D-Ser 35
VanL E. faecalis Low 8 Susceptible Chromosome Inducible D-Ala-D-Ser 36
VanM E. faecium Variable >256 0.75 Plasmid Chromosome Inducible D-Ala-D-Lac 38
VanN E. faecium Low 16 0.5 Chromosome Constitutive D-Ala-D-Ser 39, 40

MIC: minimal inhibitory concentration.

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