No abstract

Dalbavancin is a novel semi-synthetic lipoglycopeptide that was designed to improve upon the natural glycopeptides currently available, vancomycin and teicoplanin. Chemical modification of natural glycopeptides has produced compounds with more potent antimicrobial activity and longer t(1/2), while maintaining an excellent safety profile. Dalbavancin, prepared from a teicoplanin-like glycopeptide, has better activity, in vitro and in animal infection models, than vancomycin and teicoplanin. In particular, dalbavancin has excellent activity against staphylococci, including coagulase-negatives. A unique feature of dalbavancin is its pharmacokinetics, characterized by a long elimination t(1/2) in humans which makes a once-weekly dosing regimen feasible. Dalbavancin recently completed Phase 3 clinical trials in skin and skin structure infection.

The selection of a novel weekly dalbavancin dosage regimen was based on pharmacokinetic and pharmacodynamic data from humans and an animal model of infection. The results from the granuloma pouch model of infection suggested that dalbavancin concentrations >/=5 mg/L are necessary for extended in vivo activity. Serum bactericidal activity assessments demonstrated that dalbavancin serum concentrations of approximately 20 mg/L were bactericidal upon two-fold dilution. These data, coupled with simulations based on the pharmacokinetic profile derived from a clinical study in healthy volunteers, were used to design the weekly regimen studied in the initial efficacy trial. This efficacy study showed that a two-dose weekly regimen was well tolerated and associated with a higher clinical response rate than the comparator regimens. The data collectively support the further study of dalbavancin as a once-weekly regimen for the treatment of infections caused by Gram-positive bacteria.

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 serious clinical problem due to the lack of alternative and efficacious therapeutic options, particularly against infections caused by VanA strains that are highly resistant to glycopeptides and almost all other antibiotics. In addition, 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 active against these problematic organisms. The following review will focus on the development of second-generation glycopeptides, namely LY333328 (Eli Lilly) and BI 397 (Biosearch Italia, in license to Versicor for North America), which are currently undergoing clinical trials in humans for their promising activity against VanA enterococci (LY333328), staphylococci (BI 397), and penicillin-resistant pneumococci. Both compounds were identified as the result of chemical programs that were aimed at pursuing activity of vancomycin-like or teicoplanin-like natural glycopeptides 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 vancosamine is suitably replaced with other sugar moieties will also be covered.

A series of amide derivatives of natural glycopeptide A-40,926 (A), its 6B-methyl ester (MA) and 6B-decarboxy-6B-hydroxymethyl derivative (RA) were prepared with the aim of obtaining activity against glycopeptide-resistant enterococci. These compounds are structurally related to a class of amides of 34-de(acetylglucosaminyl)-34-deoxy teicoplanin which showed interesting activity against strains of Enterococcus faecalis and E. faecium highly resistant to both vancomycin and teicoplanin. Among them, RA-amides MDL63,246 and MDL63,042 were the most active derivatives against several Gram-positive bacteria, including VanB and VanC enterococci, and were moderately active (MIC range 0.5~64/ig/ml) against strains of Enterococcus for which vancomycin and teicoplanin MICswere > 128^g/ml. The chemical rationale and the synthesis of these newseries of glycopeptide derivatives are described. Preliminary in vitro data are reported and structure-activity relationships are discussed.In the last few years an increase in serious infections caused by enterococci has been observed in hospitalized patients. Clinical isolates of enterococci are intrinsically resistant to manyclasses of antibacterial drugs, and infections often require treatment with a combination of agents to which they are moderately susceptible. The recent appearance of vancomycin-resistant enterococci poses a serious threat for the near future, particularly because high-level resistance is often associated with genetic elements which can spread from one bacterial strain to another. The emerging resistance in enterococci1} is a current challenge for glycopeptides of the dalbaheptide2) family since teicoplanin (Fig. 1),3) Amongthe teicoplanin derivatives, some basic amides (Fig. 1)4) of the 34-de(acetylglucosaminyl)-34-deoxy pseudoaglycone had interesting in vitro activity against strains of Enterococcus faecalis and E. faecium highly