Oritavancin

New lipoglycopeptides (telavancin, dalbavancin and oritavancin) are in the advanced phases of clinical development. As a synthetic derivative of vancomycin, telavancin shares similar pharmacology with vancomycin. Telavancin can cause membrane depolarization and disrupt bacterial membrane barrier function by targeted interaction with cell wall precursor lipid II. Dalbavancin is a novel second-generation semi-synthetic lipoglycopeptide antibiotic which possesses in vitro activity againstMRSA. Oritavancin (known as LY333328) is a novel semi-synthetic lipoglycopeptide antibiotic with similar structure to vancomycin. The 4’-chlorobiphenylmethyl group of oritavancin contributes to its activity against gram positive bacteria.

Three other lipoglycopeptides have reached the market, oritavancin, telavancin and dalbavancin. Oritavancin differs from the parent compound, vancomycin, by the addition of a 4-epi-vancosamine sugar, which increases dimer formation and a chlorobiphenyl side-chain, which ensures membrane anchoring. Telavancin differs from vancomycin by the presence of a lipophilic decylaminoethyl tail and a phosphonomethyl-aminomethyl substituent modifying the hydrophobic/hydrophilic properties. Telavancin has a dual mechanism of action: inhibition of the transglycosylation process of peptidoglycan cell wall synthesis by the formation of a complex with the D-alanyl–D-alanine precursors and depolarization of the bacterial membrane. The latter effect requires both the presence of lipid II as well as an interaction between telavancin and D-alanyl–D-alanine residues. Dalbavancin is a teicoplanin-like glycopeptide A 40926 which shows similar spectrum of in vitro activity to the other glycopeptides, but it is more potent than teicoplanin. The monoamide (dimethylaminopropyl) substituent at the peptide carboxy group is responsible for increased potency against staphylococci, particularly against coagulase negative staphylococci. The relative activity of teicoplanin-type glycopeptides largely depends on their ionic character. The most innovative feature of dalbavancin is its pharmacokinetics. Due to the presence of the N-acylglucosamine, it exhibits excellent tissue penetration, particularly in the skin, and a long half-life that allows once-weekly administration.

Lipoglycopeptides are a class of antibiotics with a lipophilic modification. This class includes natural products such as teicoplanin, as well as semi-synthetic derivatives. Currently, the only semi-synthetic lipoglycopeptide approved by the FDA is telavancin. It is widely believed that lipoglycopeptides act against vancomycin-susceptible strains by a mechanism similar to that of vancomycin, i.e. by binding to the D-Ala-D-Ala motif. However, unlike vancomycin, some of these new agents, including telavancin and oritavancin, have rapid bactericidal activity and can be effective against strains with high-level glycopeptide resistance acquired by a modification in the D-Ala-D-Lac motif. Telavancin and oritavancin have been shown to disrupt bacterial membrane integrity and increase membrane permeability, but details of their effects at the molecular level are still elusive. Because other lipoglycopeptides, such as dalbavancin and teicoplanin, display poor activity against glycopeptide-resistant cocci, the effect of the lipophilic modification varies among side-chain structures.

Oritavancin is derived from chloroeremomycin. The key modification of natural product chloroeremomycin was the installation of a 4’-chlorobiphenylmethylene group, which affords oritavancin an additional mode of action that is absent from vancomycin; recent investigations have shown that this biaryl group is involved in cell membrane depolarisation and an increase in membrane permeability. As a consequence of this dual-action mechanism, oritavancin has excellent in vitro activity against gram positive bacteria, withMICs in the range of 0.004–1 μg mL^-1 against VRE, and is currently in phase III clinical trials funded by The Medicines Company for the treatment of acute bacterial skin and skin structure infections (ABSSSIs).