ABSTRACT
The spiropiperidylrifamycin LM 427 (4-deoxo-3,4-[2-spiro-N-isobutyl-4-piperidyl]-(1H)-imidazo-(2,5-dihydro) rifamycin S) displays a broad spectrum of potent antibacterial activity in vitro. In vivo it is particularly effective in the therapy of experimental tubercular infections of mice. Three schedules of treatment were employed and the best results were obtained when intermittent administrations were used (ED50 of LM 427; 7 times lower than rifampicin). LM 427 is well distributed in tissues of mice and rats, with lung concentrations 10 to 20 times higher than plasma levels.
Subject(s)
Rifamycins/toxicity , Animals , Bacteria/drug effects , Female , Kinetics , Mice , Mice, Inbred Strains , Microbial Sensitivity Tests , Rifabutin , Rifampin/toxicity , Rifamycins/metabolism , Species Specificity , Tissue DistributionABSTRACT
The biological properties of spiro-piperidyl-rifamycins, a new class of rifamycin antibiotics, are described. In these derivatives the positions 3 and 4 have been incorporated into an imidazolyl ring bearing a spiro-piperidyl group N substituted with linear and branched aliphatic chains. The in vitro antibacterial activity against Staphylococcus aureus and Mycobacterium tuberculosis increases with the number of the carbon atoms in the linera side chain, whereas the inhibitory effect on Escherichia coli is lowered. The antibacterial activity is only marginally affected by branching of the side chain. In vivo (experimental infections of mice) the optimal therapeutic activity against M. tuberculosis is shown by compounds bearing 3 approximately 5 carbon atoms as a linear or branched side chain; in comparison with rifampicin, the potency of these derivatives is 2 approximately 3 times higher. The finding is in a good agreement with the exceptional tissue tropism, which seems to be a favourable property of this group of derivatives.
Subject(s)
Rifamycins/pharmacology , Animals , Bacteria/drug effects , Bacterial Infections/drug therapy , Female , Kinetics , Mice , Rifabutin , Rifamycins/metabolism , Tissue DistributionABSTRACT
The biological properties of spiro-piperidyl-rifamycins, a new class of rifamycin antibiotics, are described. In these derivatives the positions 3 and 4 have been incorporated into an imidazolyl ring bearing a spiro-piperidyl group N substituted with linear and branched aliphatic chains. The in vitro antibacterial activity against Staphylococcus aureus and Mycobacterium tuberculosis increases with the number of the carbon atoms in the linera side chain, whereas the inhibitory effect on Escherichia coli is lowered. The antibacterial activity is only marginally affected by branching of the side chain. In vivo (experimental infections of mice) the optimal therapeutic activity against M. tuberculosis is shown by compounds bearing 3 approximately 5 carbon atoms as a linear or branched side chain; in comparison with rifampicin, the potency of these derivatives is 2 approximately 3 times higher. The finding is in a good agreement with the exceptional tissue tropism, which seems to be a favourable property of this group of derivatives
Subject(s)
Female , Animals , Mice , Bacteria , Kinetics , Tissue Distribution , Bacterial Infections/drug therapy , Rifabutin , Rifamycins/pharmacology , Rifamycins/metabolismABSTRACT
A new type of hydrolyzable ester of penicillin G, benzamidomethyl benzylpenicillinate (FI 7303), was studied for the antibacterial activity and kinetics of absorption in comparison with DBED-penicillin G. FI 7303 resulted to be a good repository form of penicillin G, slowly eliminated in mouse, dog and man. It exerted a remarkable therapeutic activity in mice infected with Staphylococcus aureus even when administered 26 h before infection. The protective effect in mice was more prolonged than that of DBED-penicillin G, in agreement with the longer persistence of significant blood levels.
Subject(s)
Bacteria/drug effects , Penicillin G/analogs & derivatives , Staphylococcal Infections/drug therapy , Absorption , Animals , Dogs , Drug Evaluation, Preclinical , Humans , Mice , Penicillin G/metabolism , Penicillin G/pharmacology , Penicillin G/therapeutic use , Penicillin G Benzathine/metabolism , Penicillin G Benzathine/pharmacology , Penicillin G Benzathine/therapeutic use , Penicillin Resistance , Staphylococcus aureusSubject(s)
Leucomycins/metabolism , Palatine Tonsil/metabolism , Adolescent , Adult , Child , Humans , Leucomycins/therapeutic use , Tonsillitis/drug therapyABSTRACT
The mechanism of the interference of the antiviral antibiotic distamycin A with the bacterial cell has been investigated. Labelled distamycin A is firmly bound by E. coli cells and the binding process does not require metabolic energy as indicated by the use of inhibitors. The antibiotic does not induce gross alteration in the cell membrane but inhibits cyclic AMP accumulation in the cells exposed to a glucose-free medium. This inhibition is concomitant with that exerted on the synthesis of an inducible enzyme such as beta-galactosidase. By the method of pulse induction it appears that distamycin A exterts its inhibiting effect on inducible synthesis at the level of transcription. This effect is probably related to an interference with the positive control of enzyme synthesis performed via the system represented by cyclic AMP and the CRP protein.
