ABSTRACT
Capreomycin and the structurally similar compound viomycin are cyclic peptide antibiotics which are particularly active against Mycobacterium tuberculosis, including multidrug resistant strains. Both antibiotics bind across the ribosomal interface involving 23S rRNA helix 69 (H69) and 16S rRNA helix 44 (h44). The binding site of tuberactinomycins in h44 partially overlaps with that of aminoglycosides, and they share with these drugs the side effect of irreversible hearing loss. Here we studied the drug target interaction on ribosomes modified by site-directed mutagenesis. We identified rRNA residues in h44 as the main determinants of phylogenetic selectivity, predict compensatory evolution to impact future resistance development, and propose mechanisms involved in tuberactinomycin ototoxicity, which may enable the development of improved, less-toxic derivatives.
Subject(s)
Antitubercular Agents/pharmacology , Capreomycin/pharmacology , Mycobacterium tuberculosis/drug effects , Ribosomes/drug effects , Viomycin/pharmacology , Aminoglycosides/pharmacology , Antitubercular Agents/metabolism , Antitubercular Agents/toxicity , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Capreomycin/metabolism , Capreomycin/toxicity , Drug Resistance, Multiple, Bacterial/genetics , Enviomycin/analogs & derivatives , Enviomycin/pharmacology , Enviomycin/toxicity , Mutagenesis, Site-Directed , Mycobacterium tuberculosis/genetics , Mycobacterium tuberculosis/metabolism , RNA, Ribosomal, 16S/metabolism , RNA, Ribosomal, 23S/metabolism , Viomycin/metabolism , Viomycin/toxicitySubject(s)
Antibiotics, Antitubercular/pharmacokinetics , Antibiotics, Antitubercular/toxicity , Capreomycin/pharmacokinetics , Capreomycin/toxicity , Animals , Antibiotics, Antitubercular/administration & dosage , Capreomycin/administration & dosage , Drug Contamination , Female , Humans , Lethal Dose 50 , Male , Mice , Mice, Inbred ICR , Rats , Rats, Sprague-DawleyABSTRACT
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.
