Structural Variations of the Cell Wall Precursor Lipid II and Their Influence on Binding and Activity of the Lipoglycopeptide Antibiotic Oritavancin

Münch, Daniela; Engels, Ina; Müller, Anna; Reder-Christ, Katrin; Falkenstein-Paul, Hildegard; Bierbaum, Gabriele; Grein, Fabian; Bendas, Gerd; Sahl, Hans‐Georg; Schneider, Tanja

doi:10.1128/aac.02663-14

Cited by 48 publications

(61 citation statements)

References 68 publications

(103 reference statements)

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“…These effects are also related to the capacity of oritavancin to specifically bind to lipid II, with additional interaction sites compared with its precursor chloreremomycin, which can explain its improved activity on vancomycin-resistant strains [37]. Solid-state nuclear magnetic resonance (NMR) studies have indeed shown that oritavancin possesses two binding sites on the lipid-linked disaccharide-pentapeptide monomers in S. aureus (D-Ala-D-Ala termini, like vancomycin, but also the pentaglycyl bridging segment via its lipophilic side chain on the dissacharide and components of its aglycon structure).…”

Section: Mechanism Of Action Of Lipoglycopeptidesmentioning

confidence: 99%

“…A large number of studies have examined the in vitro activity of these compounds against [17], which leads, by steric hindrance, to an inhibition of the glycan chain extension and, to a lesser extent, of crosslinking between peptidic stems. Oritavancin has additional interactions with the pentaglycyl bridge and the D-iso-glutamine residue in position 2 of the pentapeptide terminus of lipid II (zone highlighted in orange) [37], which allow it to be a stronger inhibitor of transpeptidases [38] collections of Gram-positive clinical isolates, yet many of these studies were performed using broth that was not supplemented by polysorbate-80, which is needed to prevent the adsorption of the drugs to the plastic [40][41][42]. Table 1 therefore focuses on recent studies that have used the standard procedure currently recommended by the Clinical Laboratory Standards Institute (CLSI), i.e., 0.002 % polysorbate-80 added to the culture medium [43].…”

Section: Spectrum Of Activitymentioning

confidence: 99%

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

Bambeke

2015

Drugs

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Oritavancin, telavancin, and dalbavancin are recently marketed lipoglycopeptides that exhibit remarkable differences to conventional molecules. While dalbavancin inhibits the late stages of peptidoglycan synthesis by mainly impairing transglycosylase activity, oritavancin and telavancin anchor in the bacterial membrane by the lipophilic side chain linked to their disaccharidic moiety, disrupting membrane integrity and causing bacteriolysis. Oritavancin keeps activity against vancomycin-resistant enterocococci, being a stronger inhibitor of transpeptidase than of transglycosylase activity. These molecules have potent activity against Grampositive organisms, most notably staphylococci (including methicillin-resistant Staphylococcus aureus and to some extent vancomycin-intermediate S. aureus), streptococci (including multidrug-resistant pneumococci), and Clostridia. All agents are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin, for hospitalacquired and ventilator-associated bacterial pneumonia. While telavancin is administered daily at 10 mg/kg, the remarkably long half-lives of oritavancin and dalbavancin allow for infrequent dosing (single dose of 1200 mg for oritavancin and 1000 mg at day 1 followed by 500 mg at day 8 for dalbavancin), which could be exploited in the future for outpatient therapy. Among possible safety issues evidenced during clinical development were an increased risk of developing osteomyelitis with oritavancin; taste disturbance, nephrotoxicity, and risk of corrected QT interval prolongation (especially in the presence of at-risk co-medications) with telavancin; and elevation of hepatic enzymes with dalbavancin. Interference with coagulation tests has been reported with oritavancin and telavancin. These drugs proved non-inferior to conventional treatments in clinical trials but their advantages may be better evidenced upon future evaluation in more severe infections. Key PointsNew lipoglycopeptides (telavancin, oritavancin, dalbavancin) differ from vancomycin by the presence of a lipophilic side chain, which profoundly modifies their pharmacokinetic and/or pharmacodynamic profile.Among these agents, telavancin and oritavancin have multiple modes of action and are highly bactericidal.Oritavancin and dalbavancin have prolonged halflives, allowing for their use a single-dose or twodose (once-a-week) regimen, respectively. These three drugs are indicated for the treatment of acute bacterial skin and skin structure infections, and telavancin is indicated for hospital-acquired and ventilator-associated bacterial pneumonia.

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Section: Mechanism Of Action Of Lipoglycopeptidesmentioning

confidence: 99%

Section: Spectrum Of Activitymentioning

confidence: 99%

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

Bambeke

2015

Drugs

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“…The lipoglycopeptides differ from glycopeptides in that they have lipophilic tails attached to the amino sugar, causing increased binding affinity to Lipid II and allowing them to anchor to the bacterial cell membrane. This additional mechanism causes stabilization with Lipid II, allowing them to concentrate at their site of action, increasing their potency and, for oritavancin, causing destabilization of the cell membrane, resulting in loss of membrane potential . Teicoplanin, which was introduced in Europe in 1988, was the first natural agent of this class of antibiotics.…”

Section: Lipoglycopeptidesmentioning

confidence: 99%

Dalbavancin and Oritavancin: An Innovative Approach to the Treatment of Gram-Positive Infections

2015

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Health care-associated infections, especially those caused by multidrug-resistant gram-positive organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are a growing public health threat. In 2014, the U.S. Food and Drug Administration approved two new lipoglycopeptides, oritavancin and dalbavancin, for the treatment of acute bacterial skin and skin structure infections. The rationale for the development of these antimicrobials was partly to aid in the battle against vancomycin resistance in both Staphylococcus and Enterococcus. Considered a subclass of the glycopeptide antibiotics, the new lipoglycopeptides have similar mechanisms of action of binding to the carboxyl terminal d-alanyl-d-alanine residue of the growing peptide chains but differ from their parent glycopeptides by the addition of lipophilic tails. This addition allows for these agents to have prolonged half-lives, giving them unique dosing profiles. In addition, by concentrating at the site of action, they have increased potency against MRSA compared with vancomycin, the current mainstay of therapy. In this review, we focus on comparing and contrasting these two new agents with regard to their pharmacology, mechanisms of action, spectrum of activity, safety profiles, dosage and administration, and drug and laboratory interactions, and we review the clinical trials evaluating their use.

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“…The first approved antibiotic targeting lipid II was the glycopeptide vancomycin 7 (Scheme 4). Glycopeptide antibiotics are active against a broad variety of Gram-positive pathogens and act by binding to the D-Ala-D-Ala-dipeptide terminus in lipid II on the extracellular membrane surface via several hydrogen bonds and ionic interactions (Jia et al 2013;Münch et al 2015).…”

Section: Lessons Learned From Druggable Targets In Bacteriamentioning

confidence: 99%

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

Klahn

Brönstrup

2016

Current Topics in Microbiology and Immunology

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Abstract:The development of bacterial resistance against current antibiotic drugs necessitates a continuous renewal of the arsenal of efficacious drugs. This imperative has not been met by the output of antibiotic research and development of the past decades for various reasons, including the declining efforts of large pharma companies in this area. Moreover, the majority of novel antibiotics are chemical derivatives of existing structures that represent mostly step innovations, implying that the available chemical space may be exhausted. This review negates this impression by showcasing recent achievements in lead finding and optimization of antibiotics that have novel or unexplored chemical structures. Not surprisingly, many of the novel structural templates like teixobactins, lysocin, griselimycin, or the albicidin/cystobactamid pair were discovered from natural sources. Additional compounds were obtained from the screening of synthetic libraries and chemical synthesis, including the gyrase-inhibiting NTBI s a d spiropyrimidinetrione, the tarocin and targocil inhibitors of wall teichoic acid synthesis, or the boronates and diazabicyclo[3.2

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Structural Variations of the Cell Wall Precursor Lipid II and Their Influence on Binding and Activity of the Lipoglycopeptide Antibiotic Oritavancin

Cited by 48 publications

References 68 publications

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

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

Dalbavancin and Oritavancin: An Innovative Approach to the Treatment of Gram-Positive Infections

New Structural Templates for Clinically Validated and Novel Targets in Antimicrobial Drug Research and Development

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