By combination of chemical, XKand 13C NMR,and mass spectrometric studies, the structures of the three components of the antibiotic ramoplanin (A-16686), produced by Actinoplanes sp. ATCC 33076, have been elucidated. All the components have structures formed by a commondepsipeptide skeleton carrying a dimannosyl group and are differentiated by the presence of various acylamide moieties, derived from C8, C9 and C10 fatty acids. A-16686,n an antibiotic produced by Actinoplanes sp. ATCC33076,1} is active against aerobic and anaerobic Gram-positive bacteria, including methicillin-resistant Staphylococci and bacteria resistant to ampicillin and/or erythromycin.2~5) In particular, it is very active against a series of clinical isolates of strains of Propionibacterium acnes.® Preliminary physico-chemical characterization^indicated that A-16686 is formed by a peptidic core carrying two D-mannose units. Reversed-phase high pressure liquid chromatography (HPLC) showed at an early stage that it consists of three related factors, designated Al, A2 and A3, as shown in Fig. 1. Single fac-Factor F

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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

Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria including vancomycin-resistant enterococci. Ramoplanin inhibits bacterial cell wall biosynthesis by a mechanism different from that of glycopeptides and hence does not show cross-resistance with these antibiotics. The systemic use of ramoplanin has been so far prevented because of its low local tolerability when injected intravenously. To overcome this problem, the fatty acid side chain of ramoplanin was selectively removed and replaced with a variety of different carboxylic acids. Many of the new ramoplanin derivatives showed antimicrobial activity similar to that of the natural precursor coupled with a significantly improved local tolerability. Among them the derivative in which the 2-methylphenylacetic acid has replaced the di-unsaturated fatty acid side chain (48) was selected as the most interesting compound and submitted to further in vitro and in vivo characterization studies.