Semi-synthetic glycopeptide antibiotics
Oritavancin, telavancin and dalbavancin
Early studies by Nagarajan et al. into the development of semi-synthetic glycopeptide antibiotics focused on utilizing vancomycin as a structural starting point, but the inadequate activity of vancomycin analogues led to the selection of alternatives like teicoplanin and chloroeremomycin as platforms for novel glycopeptide elaboration. Structurally similar to teicoplanin is the semi-synthetic compound dalbavancin which is appended with an additional amide group at the C-terminus. Dalbavancin has come close to clinical success, and is currently undergoing phase III clinical trials funded by Durata Therapeutics. Although its activity is similar to that of teicoplanin, the semi-synthetic compound has a remarkably long half-life of ca. 7 days as a result of strong binding to serum proteins. By comparison, vancomycin has an elimination half-life of 3–9 h. A drug that remains in the blood plasma for longer requires less frequent dosing, and is therefore clinically and economically advantageous.
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).
A derivative of vancomycin, telavancin also follows the pattern of N-alkylation of the vancosamine moiety with a hydrophobic chain, in this case a decylaminoethyl group. In addition, a methylaminophosphonate group was installed on the A-ring of the A-B biaryl region for its hydrophilic properties, which improved the absorption, distribution, metabolism and excretion (ADME) proﬁle of the compound. With excellent activity against both VRE and VRSA, telavancin was approved by the FDA in September 2009 for complicated skin and skin structure infections (cSSSI). The success of these three semi-synthetic glycopeptides as drug candidates and their potent antibacterial activities in comparison to vancomycin, has encouraged further research in the ﬁeld of glycopeptide modiﬁcation. The structure–activity relationships of telavancin, dalbavancin and oritavancin have provided valuable information about the modes of action that this class of compounds possess, with the results having a signiﬁcant inﬂuence on future drug design.
Polly-Anna Ashford, Sean P. Bew*.Chem. Soc. Rev., 2012, 41, 957–978