ABSTRACT
Two cyclic homopentapeptides, CP-101,680 and CP-163,234 [6a-(3',4'-dichlorophenylamino) analogs of viomycin and capreomycin, respectively], were identified as novel antibacterial agents for the treatment of animal disease, especially for livestock respiratory disease. The in vitro microbiological characterization of both CP-101,680 and CP-163,234 was carried out using their parent compounds, viomycin and capreomycin, as controls. This characterization included antibacterial spectrum, influence of media, inoculum size, pH, EDTA, polymixin B nonapeptide (PMBN), serum, cell-free protein synthesis inhibition, and time-kill kinetics. Our results indicated that the capreomycin analog, CP-163,234, showed slightly improved in vitro potency over the viomycin analog, CP-101,680. Both analogs showed very potent cell-free protein synthesis inhibition activity and were bactericidal against Pasteurella haemolytica, P. multocida and Actinobacillus pleuropneumoniae at the level of 4 times and 8 times MICs. CP-163,234 was bactericidal at the level of 4x and 8x MIC against E. coli, but re-growth was observed after 24 hours incubation at both concentrations of CP-101,680.
Subject(s)
Animal Diseases/drug therapy , Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Capreomycin/analogs & derivatives , Viomycin/analogs & derivatives , Animals , Capreomycin/pharmacology , Culture Media , Edetic Acid/pharmacology , Humans , Hydrogen-Ion Concentration , Microbial Sensitivity Tests , Polymyxin B/analogs & derivatives , Polymyxin B/pharmacology , Viomycin/pharmacologyABSTRACT
The tuberactinomycins are a group of cyclic peptide antibiotics, which are potent inhibitors of prokaryotic protein synthesis. We report the inhibitory effect of viomycin, di-beta-lysyl-capreomycin IIA and tuberactinomycin A on group I intron self-splicing. They compete with the guanosine cofactor for the G-binding site located in the conserved core of the intron. They are 100-fold more active than all other competitive inhibitors described so far (dGTP, arginine or streptomycin), inhibiting splicing at concentrations between 10 and 50 microM. Mutation of the G-binding site leads to partial resistance, and the inhibitory effect of these drugs is dependent on Mg2+ concentration. This suggests that the tuberactinomycins have more than one contact site with the intron RNA: via the G-binding site and via additional contacts with the RNA backbone. Positioning the tuberactinomycins in the three-dimensional model of the td intron core suggests that the charged lysyl side-chain (R1) is in contact with the backbone of the P1 helix. Structure/function analyses with various tuberactinomycin analogues with different activities confirm the involvement of this sidechain in inhibition of group I self-splicing. The demonstration of a new class of splicing inhibitors, the peptide antibiotics, illustrates how antibiotics may interact with catalytic RNA.
Subject(s)
Enviomycin/analogs & derivatives , Introns/drug effects , RNA Splicing/drug effects , Bacteriophage T4/genetics , Base Sequence , Binding Sites/genetics , Binding, Competitive , Capreomycin/analogs & derivatives , Capreomycin/pharmacology , DNA, Viral/genetics , Drug Resistance, Microbial/genetics , Enviomycin/chemistry , Enviomycin/pharmacology , Magnesium/pharmacology , Models, Molecular , Molecular Sequence Data , Mutagenesis, Site-Directed , Nucleic Acid Conformation , RNA Splicing/genetics , RNA, Viral/chemistry , RNA, Viral/drug effects , RNA, Viral/genetics , Structure-Activity Relationship , Viomycin/pharmacologyABSTRACT
Palmitoyltuberactinamine N (Pal-Tua N) and di-beta-lysylcapreomycin IIA (di-beta-Lys-Cpm IIA), which are synthetic derivatives of the antituberculous agent tuberactinomycin (Tum) and capreomycin (Cpm) respectively, were tested for anti-bacterial activity. Pal-Tua N inhibited not only tuberactinomycin-resistant Mycobacterium smegmatis but also Escherichia coli, Corynebacterium diphtheriae, Staphylococcus aureus, Streptococcus pyogenes, although it has lost activity against Mycobacterium tuberculosis. Di-beta-Lys-Cpm IIA inhibited the growth of laboratory-derived Tum-resistant M. smegmatis and M. tuberculosis as well as Tum-resistant M. tuberculosis from patients with one exceptional case.
Subject(s)
Anti-Bacterial Agents/toxicity , Capreomycin/analogs & derivatives , Enviomycin/toxicity , Viomycin/toxicity , Bacteria/drug effects , Capreomycin/toxicity , DNA-Directed RNA Polymerases/metabolism , Enviomycin/analogs & derivatives , Microbial Sensitivity Tests , Mycobacterium/drug effects , Ribosomes/drug effects , Species Specificity , Structure-Activity Relationship , Transcription, Genetic/drug effectsABSTRACT
The effects of 61 synthetic tuberactinomycin derivatives on polypeptide synthesis were tested in bacterial cell-free systems. Di-beta-lys-capreomycin IIA was more effective than the natural product. Palmitoyl tuberactinamine N inhibited the growth of tuberactinomycin-resistant mutants and was not a ribosome inhibitor.
