Glycopeptide derivatives

Resistance to glycopeptides in enterococci, which first emerged in the late 1980's and is now widespread mainly in the United States, is posing a seri ous clinical problem due to the lack of alternative and efficacious therape utic options, particularly against infections caused by VanA strains that a re highly resistant to glycopeptides and almost all other antibiotics. In a ddition, isolates of Staphylococcus aureus, known as GISA, that are poorly susceptible to vancomycin and teicoplanin have been identified. Thus, there is an urgent need to develop new and more potent glycopeptides that are ac tive against these problematic organisms. The following review will focus on the development of second-generation gly copeptides, namely LY333328 (Eli Lilly) and BI 397 (Biosearch Italia, in li cense to Versicor for North America), which are currently undergoing clinic al trials in humans for their promising activity against VanA enterococci ( LY333328), staphylococci (BI 397), and penicillin-resistant pneumococci. Bo th compounds were identified as the result of chemical programs that were a imed at pursuing activity of vancomycin-like or teicoplanin-like natural gl ycopeptides against VanA enterococci and multidrug-resistant staphylococci. More recent approaches toward glycopeptides modified in their heptapeptide core are also described. These include compounds in which amino acids 1 and 3 are replaced with other amino acid moieties such as in the modification of the asparagine side chain on residue 3 as well as attempts to change the structure of the heptapeptide backbone in positions that are critical for the molecular interaction with susceptible D-Ala-D-Ala and resistant D-Ala- D-Lactate targets. Covalently linked glycopeptide dimers and vancomycin derivatives in which v ancosamine is suitably replaced with other sugar moieties will also be cove red.