Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

Abstract

The emergence and spread of multidrug-resistant gram-positive bacteria represent a serious clinical problem. Telavancin is a novel lipoglycopeptide antibiotic that possesses rapid in vitro bactericidal activity against a broad spectrum of clinically relevant gram-positive pathogens. Here we demonstrate that telavancin's antibacterial activity derives from at least two mechanisms. As observed with vancomycin, telavancin inhibited latestage peptidoglycan biosynthesis in a substrate-dependent fashion and bound the cell wall, as it did the lipid II surrogate tripeptide N,N-diacetyl-L-lysinyl-D-alanyl-D-alanine, with high affinity. Telavancin also perturbed bacterial cell membrane potential and permeability. In methicillin-resistant Staphylococcus aureus, telavancin caused rapid, concentration-dependent depolarization of the plasma membrane, increases in permeability, and leakage of cellular ATP and K ؉ . The timing of these changes correlated with rapid, concentration-dependent loss of bacterial viability, suggesting that the early bactericidal activity of telavancin results from dissipation of cell membrane potential and an increase in membrane permeability. Binding and cell fractionation studies provided direct evidence for an interaction of telavancin with the bacterial cell membrane; stronger binding interactions were observed with the bacterial cell wall and cell membrane relative to vancomycin. We suggest that this multifunctional mechanism of action confers advantageous antibacterial properties.The emergence and spread of bacterial resistance to vancomycin, an important antibiotic used to treat serious infections caused by gram-positive bacteria, has prompted active research to discover new glycopeptides and semisynthetic analogs with improved antimicrobial properties. Vancomycin and related glycopeptide antibiotics inhibit cell wall synthesis in susceptible bacteria by binding with high specificity to peptidoglycan precursors containing the C-terminal D-alanyl-D-alanine (D-Ala-DAla) motif (8). The peptide portion of glycopeptide antibiotics forms a carboxylate binding pocket that imparts, through a combination of five hydrogen bonds plus favorable hydrophobic interactions, strong affinity for the D-Ala-D-Ala-containing terminus of lipid II (8,46,54). Rational approaches toward the design of glycopeptides with improved antimicrobial activities have been described previously (for reviews, see references 35 and 36). One promising approach has been the discovery of lipoglycopeptides, analogs containing hydrophobic groups substituted at the amine position of the disaccharide moiety (20,39,40,45).Telavancin, a semisynthetic derivative of vancomycin possessing a hydrophobic (decylaminoethyl) side chain appended to the vancosamine sugar and a hydrophilic [(phosphonomethyl)aminomethyl] group on the resorcinol-like 4Ј position of amino acid 7 (33), is in late-stage clinical development for the treatment of serious gram-positive infections. Telavancin and other lipoglycopeptides exhibit superior in vitro activity compa...

Lipoglycopeptide Antibacterial Agents in Gram-Positive Infections: A Comparative Review

“…Membrane anchoring has been documented for both oritavancin and telavancin via their lipophilic side chain linked to the disaccharide moiety [29,30]. Both molecules also cause aberrant septum formation and loss of staining of nascent septal cross walls in electron microscopy, which may result from their effect on cell wall synthesis and/or activation of autolysins [31].…”

“…For telavancin, a specific, high-affinity interaction with lipid II has been demonstrated, leading to membrane depolarization, bacterial lysis, and rapid bactericidal effect [30,33]. Microarray analyses revealed that after 15 min of exposure to the drug a strong expression of the cell wall stress stimulon (characteristic response to inhibition of cell wall biosynthesis), which was accompanied after 60 min of exposure by an induction of various genes, was also affected by other membrane-depolarizing drugs [34].…”

Telavancin: A Review of its Use in Treating Gram-Positive Infections

“…1). 8 Telavancin has superior in vitro activity compared to vancomycin and has rapid concentration-dependent bactericidal activity against glycopeptide-susceptible organisms and those with intermediate glycopeptide sensitivity.…”

“…This is likely to account for the 10-fold greater potency in inhibition of peptidoglycan synthesis of telavancin compared to vancomycin, despite a lower calculated affinity relative to vancomycin for binding a D-Ala-D-Ala containing target in solution. 8 A study by Lunde and colleagues used fluorescence microscopy to demonstrate that telavancin showed enhanced binding to the division septum compared with vancomycin. 16 If inhibition of cell wall synthesis was the only mechanism of action for telavancin then it would be expected to have a slow bactericidal effect.…”

“…7 It has a dual mechanism of action and disrupts both cell wall synthesis and cell membrane integrity. 8 Telavancin has antimicrobial activity against a wide range of Gram-positive organisms including MRSA and some VRE [9][10][11] and has been used to treat patients with cSSSIs, [12][13][14] hospital-acquired pneumonia and ventilator-associated pneumonia. 15 In this review we will outline the mechanisms of action, antimicrobial spectrum, pharmacokinetics, clinical use and safety aspects of telavancin, and discuss its potential role in the antimicrobial armamentarium.…”