Chemistry and Pharmacology
Telavancin, a semisynthetic derivative of the glycopeptide vancomycin, is structurally similar to the glycopeptides but has an additional hydrophobic and hydrophilic moiety (Figure 1). Specifically, telavancin contains a lipophilic (decylaminoethyl) side chain attached to the vancosamine sugar, as well as a hydrophilic ([phosphonomethyl]aminomethyl) group on the 4' position of amino acid 7.[14] The addition of the lipophilic decylaminoethyl substituent to the molecule classifies this agent as a lipoglycopeptide.
Figure 1.
Chemical structures of telavancin and vancomycin.
Telavancin has two proposed mechanisms of action (Figure 2). The first mechanism is similar to vancomycin´s and involves highly specific, noncovalent binding to the terminal D-Ala-D-Ala stem peptides of both lipid II and immature, un-cross-linked glycan strands.[15] This binding shields substrates from transglycosylases and transpeptidases; thus, peptidoglycan polymerization and cross-linking steps are inhibited. The second proposed mechanism of action involves depolarization of the bacterial membrane, resulting in disruption of the functional integrity of the bacterial membrane. It is speculated that this secondary mechanism of action depends on the interaction of the lipophilic decylaminoethyl moiety of telavancin with the lipid bilayer of the bacterial cell membrane.[16] The effect of telavancin on membrane potential in bacterial cells was observed at a concentration of approximately 16 mg/L; this concentration is higher than telavancin´s minimum inhibitory concentration (MIC) against most gram-positive isolates.[15] This dual mechanism of action is of particular interest, since few other glycopeptides are believed to work in this manner.
Figure 2.
Mechanisms of action of telavancin. The top panel demonstrates normal cell-wall synthesis of a gram-positive bacterium with the production of peptidoglycan strands from lipid II by transglycosylase and the cross-linking of glycan strands by transpeptidase. The center panel demonstrates telavancin inhibiting transglycosylase and transpeptidase, thus inhibiting the polymerization of peptidoglycan from lipid II and cross-linking of peptidoglycan strands into the bacterial cell wall. The third panel demonstrates telavancin´s secondary mechanism of action, whereby telavancin noncovalently binds to a membrane-bound molecule of lipid II in a recently divided gram-positive bacteria (inset) and the lipophilic decylaminoethyl moiety of the molecule interacts directly with the bacterial cell membrane. This interaction results in increased membrane permeability and depolarization of the bacterial cell membrane. Illustration by Taina Litwak, CMI.
Am J Health Syst Pharm. 2007;64(22):2335-2348. © 2007 American Society of Health-System Pharmacists
Cite this: Telavancin: A Novel Lipoglycopeptide Antimicrobial Agent - Medscape - Nov 15, 2007.
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