Glycopeptide antibiotics modifications

Chemical modification of glycopeptide antibiotics with macrocyclic aglycones 98MI48. 

Malabarba A, Nicas TI, Thompson RC (1997) Structural modifications of glycopeptide antibiotics. Med Res Rev 17 69-137... 

STRUCTURAL MODIFICATIONS OF GLYCOPEPTIDE ANTIBIOTICS AND STRUCTURE ACTIVITY RELATIONSHIP (SAR) STUDIES... 

Scheme 2-9. Semisynthetic modifications of vancomycin-type glycopeptide antibiotics, (a) Alterations and modifications of amino acids, (b) Attachment of molecules to the amino groups, to the carboxy groups, and to phenolic carbohydrate functionalities. Similar modifications have been performed for antibiotics of the teicoplanin-type.

Glycopeptide antibiotics have been found to be very effective chiral selectors in the enantiomeric separation of racemic pharmaceutical compounds. Vancomycin, ristocetin A, rifamycins, teicoplanin, kanamycin, streptomycin, and avoparcin have been added to the running buffer to obtain enantioseparation (161,203— 207). A few technical modifications, such as coated capillaries and separation conditions in the reverse polarity mode (as opposed to normal polarity mode, where the flow is from anode to cathode) were found to improve sensitivity and increase efficiency (116,208). 

The modification and biological profiling of potentially useful bio active natural products is a very important goal. By applying CuAAC in the last step of derivatization, Walsh et al. prepared a library of the glycopeptide antibiotic tyrocidine [80]. 

Ciabatti R, Malabatba A. Glycopeptide antibiotics and their structural modifications. La Chimiea e L industria 1994 76 300-304. 

Pavlov AY, Olsfyeva EN. Berdnikova TF, Maikova V, Probrazhenskaya MN. Modification of glycopeptide antibiotic eremomycin by the action of alkyl halides and study on antibacterial activity of the compounds obtained. J Antibiot 1994 47 225-232. 

The originally nonbiased modifications of glycopeptide molecules used in SAR studies together with the knowledge on the mode of action, stimulated researchers to develop more rational and sophisticated approaches and concepts to raise antibiotic activity of glycopeptide derivatives also against glycopeptide-resistant bacterial strains. A selection of these approaches is discussed in the subsequent sections. 

With the emergence of bacterial strains that are resistant to these glycopeptides, the first line of defense is often to synthetically modify the natural antibiotic. In the case of these glycopeptides, synthetic alteration of the aglycone stmcture is not practical, due to their complexity. However, the carbohydrate portion of the molecule [vancosamine(a l-2)glucose in the case of vancomycin] is readily accessible to modification. This strategy has led to new antibiotics that have potential for treatment of vancomycin-resistant strains. 

Vancomycin is an antibiotic of last resort for life-threatening enterococcal and staphylococcal infections, such as methicillin-resistant Staphylococcus aureus (MRSA). Numerous natural and semisynthetic glycopeptide analogs have since been synthesized [47]. However, the main emphasis was placed on the modification of the peripheral features of vancomycin, but the characteristic tricyclic... 

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