Reductive Alkylation of Glycopeptide Antibiotics: Synthesis and Antibacterial Activity.

Cooper, R. D. G.; Snyder, Nancy; Zweifel, Mark J.; Staszak, Michael A.; Wilkie, Stephen C.; Nicas, Thalia I.; Mullen, D. L.; Butler, Thomas F.; Rodriguez, Michael J.; Huff, Bret E.; Thompson, Richard C.

doi:10.7164/antibiotics.49.575

Cited by 178 publications

(130 citation statements)

References 14 publications

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“…LY333328 is an investigational N-alkyl semisynthetic derivative of the naturally occurring glycopeptide LY264826 (56). Its mechanism of action is still unknown but is thought to be similar to that of vancomycin.…”

Section: Treatmentmentioning

confidence: 99%

Vancomycin-Resistant Enterococci

Çetinkaya

Falk

Mayhall

2000

Clinical Microbiology Reviews

642

344

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Section: Treatmentmentioning

confidence: 99%

Vancomycin-Resistant Enterococci

Çetinkaya

Falk

Mayhall

2000

Clinical Microbiology Reviews

642

344

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“…Chloroeremomycin differs from vancomycin by the presence of an additional aminated sugar (4-epi-vancosamine) on the amino acid 6 of the cyclic heptapeptide and the replacement of the 4-vancosamine by a 4-epi-vancosamine in the disaccharide attached to the aglycone moiety [1]. In oritavancin, the addition of a chlorobiphenylmethyl side chain to this disaccharide is responsible for the amphipathic character of the molecule.…”

Section: Oritavancinmentioning

confidence: 99%

“…Oritavancin was discovered at Eli Lilly [1] as LY333328 (see Allen [2] for a full history of this molecule). It was selected as a candidate for clinical development in 1994 based on its excellent activity in vitro and in vivo as well as on a favorable pharmacokinetic profile.…”

Section: Oritavancinmentioning

confidence: 99%

“…An early work [24] suggested that the interaction between glycopeptides and the D-Ala-D-Ala motif can be enhanced by two mechanisms, namely (a) the formation of homodimers between glycopeptide molecules, which confers a structural rigidity that locks the binding pocket into the correct conformation and may allow for a cooperative binding to the ligand, and (b) the anchoring of the antibacterial in the membrane, which may help to maintain the drug close to its target (see Van Bambeke et al [25] for a review). Dimer formation has been shown to occur with oritavancin [1,26] via the additional 4-epi-vancosamine sugar, putting the molecule in a back-to-back orientation and allowing cooperative binding to the ligand. Dalbavancin also strongly dimerizes in solution, and even in the absence of a ligand [27,28], but via lipophilic side chains.…”

Section: Mechanism Of Action Of Lipoglycopeptidesmentioning

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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“…In parallel, derivatives of vancomycin substituted by an alkyl side chain on their vancosamine sugar showed also enhanced activity on resistant strains (15). Combining these two features, oritavancin (initially LY333328; Eli Lilly, Indianapolis, IN, USA) was first described in 1996 (16) as the chlorobiphenylmethyl side chain analog of chloroeremomycin ( Figure 1). As compared to vancomycin, this antibiotic shows higher intrinsic activity (lower MICs) (Table II) against susceptible Gram-positive organisms, as well as against staphylococci displaying the VISA phenotype or even against VRE (vancomycin-resisitant enterococci) or VRSA (vancomycin-resistant S. aureus) (17,18).…”

mentioning

confidence: 99%

Renaissance of antibiotics against difficult infections: Focus on oritavancin and new ketolides and quinolones

Bambeke

2014

Annals of Medicine

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Reductive Alkylation of Glycopeptide Antibiotics: Synthesis and Antibacterial Activity.

Cited by 178 publications

References 14 publications

Vancomycin-Resistant Enterococci

Vancomycin-Resistant Enterococci

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

Renaissance of antibiotics against difficult infections: Focus on oritavancin and new ketolides and quinolones

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