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.

A series of derivatives of rifamycin P, an antibiotic produced by fermentation of a mutant strain of Nocardia mediterranea or by chemical modification of rifamycin S, have been prepared. The structures of these compounds were determined by 1H NMR, IR, UV, and LC/MS. Their in vitro and in vivo antibacterial activities in comparison with rifampicin and two other rifamycins under investigation were evaluated. The derivatives were more active than rifamycin P against Mycobacterium avium complex and other slowly and rapidly growing nontuberculous mycobacteria which frequently cause systemic infection in patients with AIDS. 2'-(Diethylamino)rifamycin P (P/DEA) appears suitable for further investigation.

A series of peptide derivatives of teicoplanin A2 (CTA) and deglucoteicoplanin (TD) was prepared by condensation of the 63-carboxyl function with the a-amino group of selected amino acids and their derivatives.The modification of the ionic character of CTAand 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.Teicoplanin,1) a glycopeptide antibiotic recently introduced in therapeutic use for the parenteral treatment of severe infections caused by Gram-positive bacteria,2) has been extensively studied clinically in the past few years. It was also submitted to chemical modifications aiming at improving the activity against coagulase-negative Staphylococci (CNST) and at broadening the antibacterial spectrum of activity to Gram-negative organisms. The possibility of obtaining teicoplanin derivatives active by oral route was also investigated.As a preliminary approach, the sugars of teicoplanin A2 (CTA) were hydrolyzed, under acidic conditions, to give the pseudo-aglycones T-A3-1 (TB) and T-A3-2 (TC), and the aglycone (TD, Fig. 1).3'4) Though to a different extent, these compounds still possessed antimicrobial activity. In particular, TDwas more in vitro active than CTAagainst CNSTand had a certain activity against Gram-negative bacteria.3)As for the other glycopeptide antibiotics of the vancomycin-ristocetin family, the mechanismof action of teicoplanin consists in the inhibition of the biosynthesis of bacterial peptidoglycan through a complex formation with the terminal D-alanyl-D-alanine of muramyl pentapeptide.5) The synthesis of some ester derivatives of TC and TD6) and of a series of amides of CTA, TB, TC and TD7) indicated that the carboxyl group is not directly involved in the binding with the target peptide. These modifications also led to compounds with better biological properties than those of the corresponding unmodified antibiotics. In particular, some basic amides ofTD were more in vitro active than TDagainst Gram-negative organisms, and some basic amides of CTAwere more in vitro active than CTAagainst CNSTand more in vivo effective than CTAin experimental Streptococcus pyogenes septicemia in the mouse, by oral route. In this paper a series of 7V63-carboxypeptides of CTAand TDwith acidic, neutral, basic amino acids and their derivatives is described. ChemistryCondensation of the 63-carboxyl group ofCTA ( Fig. 1) with the a-amino group of selected amino acids was carried out according to the procedures outlined in Schemes1 and 2.

Die Reaktion von Rifamycin S (I) mit Cysteinamid (II) gibt das Thiazolrifamycin (IIIa).

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