teicoplanin-aglycone and Streptococcal-Infections

Basic carboxamides of teicoplanin A2 (CTA) and its aglycon (TD) are prepared by condensation of the 63-carboxyl function of these antibiotics with linear or branched polyamines. The antimicrobial activities of some of the resulting compounds were better than those of the unmodified antibiotics. The presence of more than one basic group in the amidic chain enhanced the in vitro activity of some TD-amides against Gram-negative bacteria; two of these derivatives were also effective in vivo against Escherichia coli septicemia in the mouse. Among the CTA derivatives, the amide with spermine showed some unexpected in vitro activity against Gram-negatives. Both CTA- and TD-amides with polyamines are very soluble in water over a wide range of pH and are very hydrophilic.

Topics: Amides; Amino Acid Sequence; Animals; Bacteremia; Escherichia coli Infections; Mice; Microbial Sensitivity Tests; Molecular Sequence Data; Oligopeptides; Polyamines; Protein Binding; Streptococcal Infections; Streptococcus pyogenes; Structure-Activity Relationship; Teicoplanin

A series of 34-de(acetylglucosaminyl)-34-deoxy derivatives of 34,35- and 35,52-didehydro teicoplanin antibiotics have been synthesized from teicoplanin and its N-acetylglucosamine containing pseudoaglycons under basic conditions. The structures of these compounds have been determined by 1H NMR, UV, and FAB-MS. 35,52-Unsaturated derivatives maintained in vitro and in vivo antimicrobial activity to a different extent as well as the ability for binding to Ac2-L-Lys-D-Ala-D-Ala, a bacterial cell-wall model for the site of action of glycopeptide antibiotics. In contrast, 34,35-unsaturated compounds were markedly less active and possessed a negligible affinity for the synthetic tripeptide.

Topics: Acetylglucosamine; Animals; Anti-Bacterial Agents; Bacteria; Chemical Phenomena; Chemistry; Enterobacteriaceae; Glucosamine; Glycopeptides; Magnetic Resonance Spectroscopy; Mass Spectrometry; Mice; Molecular Structure; Oligopeptides; Peptidoglycan; Pseudomonas aeruginosa; Spectrophotometry, Ultraviolet; Staphylococcus; Streptococcal Infections; Streptococcus; Teicoplanin

The condensation of the carboxyl function of teicoplanin A2 (CTA) and its acidic hydrolysis pseudoaglycons (TB, TC) and aglycon (TD) with amines carrying various functional groups and chains produced amide derivatives with different isoelectric points and lipophilicities. Amide formation did not affect the ability of these compounds to bind to Ac2-L-Lys-D-Ala-D-Ala, a model for the natural peptide binding site in bacterial cell walls. The antimicrobial activities of teicoplanin amides were found to depend mostly on their ionic and lipophilic character and on the type and number of sugars present. Positively charged amides were generally more in vitro active than the respective unmodified antibiotics against Gram-positive organisms. In particular, most basic amides of CTA were markedly more active than teicoplanin against coagulase-negative staphylococci. A few amides of TC and most of those of TD also showed a certain activity against Gram-negative bacteria. In experimental Streptococcus pyogenes septicemia in the mouse, some basic amides were more active than the parent teicoplanins when administered subcutaneously. Some of those of CTA were also slightly more effective than teicoplanin by oral route.

Topics: Amides; Animals; Anti-Bacterial Agents; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Glycopeptides; Isoelectric Focusing; Mice; Peptides; Streptococcal Infections; Structure-Activity Relationship; Teicoplanin

A series of peptide derivatives of teicoplanin A2 (CTA) and deglucoteicoplanin (TD) was prepared by condensation of the 63-carboxyl function with the alpha-amino group of selected amino acids and their derivatives. The modification of the ionic character of CTA and TD influenced their in vitro and in vivo antimicrobial properties to a different extent, depending on the structure of the amino acidic moiety at C-63. A certain effect on binding strength to Ac2-L-Lys-D-Ala-D-Ala, a synthetic model of the antibiotic's target peptide, was also observed.

Topics: Animals; Anti-Bacterial Agents; Chemical Phenomena; Chemistry; Chromatography, High Pressure Liquid; Glycopeptides; Gram-Positive Bacteria; Mice; Microbial Sensitivity Tests; Molecular Sequence Data; Peptides, Cyclic; Sepsis; Streptococcal Infections; Structure-Activity Relationship; Teicoplanin