Synthesis and biological activity of N63-carboxypeptides of teicoplanin and teicoplanin aglycone.

Abstract

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.

Structural modifications of glycopeptide antibiotics

“…e. Carboxypeptides. For teicoplanin amides and hydrazides, the antibacterial activity of peptide derivatives [ Fig.12(k)], 70 obtained by condensation of the carboxyl group of CTA or TD and their derivatives with the ␣-amino group of selected amino acids, depended primarily on their ionic and lipophilic character. A significant increase in the in vitro and in vivo activities relative to parent antibiotics was observed with carboxypeptides with isoelectric points in the range of 8.2 to 9.0, while no improvement was shown by acidic, neutral, or more basic derivatives.…”

“…The ristocetin group has aromatic amino acids present at both positions, and has an ether linkage joining these two amino acids. The teicoplanin antibiotics have the same peptide core as the ristocetin group, but have sugars 70 MALABARBA, NICAS, AND THOMPSON…”

Antibacterial glycopeptide antibiotics (review)

“…The most interesting were the amides of dalbaheptides, although the esters [69][70][71], hydrazides [72], and carboxypeptides [73] exhibited high activity both /n vitro and in rivo. The amides of eremomycin, the activity of which in vivo is comparable with the activity of the initial antibiotic, unlike the latter did not exhibit histamine-releasing activity [74].…”

New semisynthetic teicoplanin derivatives have comparable in vitro activity to that of oritavancin against clinical isolates of VRE

“…Practically, hardly any of the publications describing the classical modifications of teicoplanin (e.g. deglycosylation [8], N-alkylation [9], ester and amide formation [10,11], a combination of these [12], N-acylation [13], synthesis of thioureas [14], etc.) mention activities against teicoplanin resistant strains, which might be due to the less common occurrence of VanA type enterococci at that time.…”

“…The transformation of the terminal carboxyl function of teicoplanin-like antibiotics into different amides with basic character is known to frequently enhance the antibacterial activity and in vivo efficacy [11]. The improvement is usually more observable against staphylococci, but the susceptibility of resistant enterococci to such amide derivatives is also likely to increase, as it was demonstrated in the case of the structurally related antibiotic A-40926 [16].…”