The effect of 4 vancomycin antibiotics on factor VIII-dependent agglutination of thrombocytes was studied. Significant similarity, both quantitative and qualitative, between ristocetin and ristomycin was found. In this connection ristomycin may be used for determination of the so-called ristocetin cofactor. Actinoidin and vancomycin inhibited agglutination of platelets induced by ristocetin or ristomycin in platelet-enriched plasma with citrate or EDTA the same as in the system contaning platelets treated with formalin and did not inhibit agglutination induced by the bovine factor VIII. The 4 antibiotics induced precipitation of the plasma protein. Vancomycin was most active and actinoidin ws lest active in this respect. Ristocetin and ristomycin also possessed such capacity, the effect of the latter being higher. Actinoidin and vancomycin did not prevent the immediate effect of light absorption increasing due to addition of ristocetin or ristomycin to fixed platelets in concentrations completely inhibiting agglutination of platelets in the presence of the protein cofactor. Inhibition of this direct effect of ristocetin and ristomycin was observd only at higher concentrations, which indicated that this effect was not probably associated with agglutination. The results of the study on various ristomycin derivatives showed that methylated carboxylic groups and free hydroxyls of phenol may play the main role in ristomycin binding with the thrombocytic membrane and/or protein cofactor.
Des-(N-methyl-d-leucyl)eremomycin was obtained by Edman degradation of eremomycin. Derivatives with a hydrophobic substituent at the exterior of the molecule were then synthesized, and their antibacterial activities were compared with similar derivatives of eremomycin. Comparison of derivatives of eremomycin containing the n-decyl or p-(p-chlorophenyl)benzyl substituent in the eremosamine moiety (N') and n-decyl or p-(p-chlorophenyl)benzylamides with similar derivatives of eremomycin possessing the damaged peptide core (a defective binding pocket) showed that compounds of both types are almost equally active against glycopeptide-resistant strains of enterococci (GRE), whereas eremomycin derivatives are more active against staphylococci. Hydrophobic 7d-alkylaminomethylated derivatives of eremomycin (9, 10) demonstrated similar antibacterial properties. Since the basic mode of action of glycopeptide antibiotics involves binding to cell wall intermediates terminating in -d-Ala-d-Ala and this interaction is seriously decreased in the hexapeptide derivatives (lacking the critical N-methyl-d-leucine), we suggest that these hydrophobic derivatives may inhibit peptidoglycan synthesis in the absence of dipeptide binding. NMR binding experiments using Ac-d-Ala-d-Ala show that binding constants of these hexapeptide derivativies are decreased in comparison with the corresponding heptapeptides with intact binding pocket. This is in agreement with the decreased biological activity of the hexapeptide derivatives against vancomycin-sensitive strains in comparison with the activity of parent compounds. Binding to the lactate cell wall analogue Ac-d-Ala-d-Lac with decylamide of eremomycin 8 was not observed, demonstrating that the interaction with this target in GRE does not occur. While hydrophobic glycopeptide derivatives retain the ability to inhibit the synthesis of peptidoglycan in manner of natural glycopeptides, biochemical investigation supports the hypothesis that they inhibit the transglycosylase stage of bacterial peptidoglycan biosynthesis even in the absence of dipeptide or depsipeptide binding.
Elsőkent alkalmaztunk negyszogsavesztereket uj antraciklin-glikozid (adriamicin, daunomicin, carminomicin) es glikopeptid (eremomicin,vankomicin,riszticetin, teikoplanin) antibiotikomok es szarmazekaik szintezisere.Eljarasunkat az aminodeoxi-cukrokra (es alditolokra,amino-aldonsavakra, es glikozilaminokra) is kiterjesztettuk, amely lehetőseget kinal uj ciklitol-antibiotikumok es specifikus horgony (spacer,linker) vegyuletek stb... előallitasara.Kuzuluk az adriamicin(SA-17) szarmazek jelentős sargalaz es dengue-virus ellenes hatasunak bizonyult.Egy specialis hidrofob-csoporttal szubsztitualt-aglikorisztocetin(8e) influenza ellenes aktivitasa pedig felulmulta a forgalomban levő leghatasosabb keszitmenyt az Oseltamivirt.Sikerult olyan N- glikozil- aglikorisztocetin szarmazekot keszitenunk, amely megtartotta az anyavegyulet aktivitasat, de a nem aggregalta a trombocytakat. A Xenorhabdus ssp. Var. Bicornutus (belbakteriumanak) tenyeszeteből egy arginin tartalmu heptapeptidet izolatunk es tanulmanyoztuk mezőgazdasagi felhasznalasanak lehetőseget. | We were the first to apply squaric acid esters for the synthesis of new anthracycline glycoside- (adriamycin, daunomycin, carminomycin) and vancomycin-type (eremomycin,vancomycin, ristocetin, teicoplanin) antibiotics and their derivatives. We extended the procedure also for the preparation of aminodeoxy sugars (and alditols, amino aldonic acids, glycosylamines), and this offers possibilities for obtaining new cyclitol antibiotics and specific anchor (spacer, linker, etc.) compounds. Of these substances, the adriamycin derivative SA-17 possesses significant activity against yellow fever and the dengue-virus. The anti-influenza activity of an aglyco-ristocetin derivative (8e), carrying a specific hydrophobic substituent, was higher than the most effective commercial preparation; Oseltamivir. We succeeded to synthesize an N-glycosyl aglyco-ristocetin derivative which retained the activity of the parent antibiotic but did not cause thrombocyte aggregation. We isolated an arginin-containing heptapeptide from the culture of the intestinal bacterium Xenorhabdus sp. Var. Bicornutus and studied its possible utilization in agricultural practice.
