The inhibition of pepsin, cathepsin D and renin by pepstatins, pepstanone A and their partial peptides is described. A new method using a nonapeptide containing 3H-Val as the substrate was devised for determination of renin activity. The pepstatin partial peptides valyl-valyl-4-amino-3-hydroxy-6-methylheptanoic acid (Val-Val-AHMHA), isovaleryl-valyl-valyl-4-amino-3-hydroxy-6-methylheptanoic acid (IVA-Val-Val-AHMHA) and carbobenzoxyvalyl-valyl-4-amino-3-hydroxy-6-methylheptanoic acid (Z-Val-Val-AHMHA) weakly inhibited proteolysis by pepsin and did not inhibit renin. Pepstatins B, C, E and G were as active as pepstatin A against pepsin and were slightly more active against renin than pepstatin A. Pepstanone A was as active as pepstatin A against pepsin but slightly less active against renin.
BB-K8 is a new derivative of kanamycin acylated with L(-)-γ-amino-α-hydroxybutyric acid at the C-1 amino group of the 2-deoxystreptamine moiety. The details of the synthesis, involving a selective acylation of kanamycin, as well as the structural proof for BB-K8 are described. BB-K8 has antibacterial activity generally equal to kanamycin against kanamycin-sensitive organisms and is also active against kanamycin- and/or gentamicin-resistant organisms, including Pseudomonas strains. It gives good protection against experimental infections in mice with both kanamycin-sensitive and resistant organisms. BB-K8 is not orally absorbed but gives high blood levels after par enter al administration and is excreted unchanged in the urine. BB-K8 is less toxic than kanamycin in terms of acute intravenous LD50.
BB-K8 is a new semisynthetic aminoglycoside antibiotic that has an extremely broad spectrum of antimicrobial activity which is due, at least in part, to the compound's high degree of resistance to aminoglycoside-inactivating enzymes. The new derivative inhibited 99.7% of 308 clinical isolates of Enterobacteriaceae, 100% of 97 Staphylococcus aureus strains, and 94.5% of 110 Pseudomonas sp. in in vitro tests at concentrations achievable in serum following administration of safe doses to humans. Of 23 strains of Pseudomonas sp. found resistant to gentamicin, 17 were susceptible to BB-K8 indicating an absence of complete cross-resistance between these antibiotics. BB-K8's bactericidal potential, as well as its response to changes in inoculum size and variations in medium constituents, were similar to those of kanamycin and gentamicin. As has been reported for gentamicin, combinations of BB-K8 with carbenicillin give a high incidence of synergistic responses against Pseudomonas strains. BB-K8 was well absorbed by mice when administered by the intramuscular route and was less toxic than kanamycin. In experimental infections of mice, BB-K8 was as active as kanamycin in infections caused by kanamycinsensitive bacteria. In addition, it was highly efficacious in infections produced by kanamycin- and/or gentamicin-resistant organisms.
An increasing number of antibiotics has been reported in the last few years to be active on 80S type ribosomes1, 2, 3, 4). However taking into account the scarcity of data concerning the site and mode of action of these antibiotics and the enormous heterogeneity of the biological sources of 80S type ribosomes in which they were tested we have considered of interest surveying a number of inhibitors in different steps of protein synthesis using in all cases the same mammalian cell-free system. We summarize in this contribution suitable methods to study the individual steps of protein synthesis by human tonsil ribosomes and present the results obtained in these systems in the presence of a number of protein synthesis inhibitors.