RESUMO
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.
Assuntos
Antituberculosos/farmacologia , Capreomicina/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Ribossomos/efeitos dos fármacos , Viomicina/farmacologia , Aminoglicosídeos/farmacologia , Antituberculosos/metabolismo , Antituberculosos/toxicidade , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Capreomicina/metabolismo , Capreomicina/toxicidade , Farmacorresistência Bacteriana Múltipla/genética , Enviomicina/análogos & derivados , Enviomicina/farmacologia , Enviomicina/toxicidade , Mutagênese Sítio-Dirigida , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , RNA Ribossômico 16S/metabolismo , RNA Ribossômico 23S/metabolismo , Viomicina/metabolismo , Viomicina/toxicidadeRESUMO
The relationships between degrees of ototoxicity and the chemical structures of ototoxic drugs were investigated using isolated bullfrog semicircular canals. Thirteen derivatives of tuberactinomycin (Tum), a peptide antibiotic with pharmacological characteristics similar to those of kanamycin, were prepared by replacing the R1 branch with various amino acids. The degrees of ototoxicity were measured in these derivatives as well as in different kinds of aminoglycoside (AGs) antibiotics (TOB, GM, NTL, ISP, AMK). In order to measure the degree of ototoxicity, the ampullary nerve action potential of isolated bullfrog posterior semicircular canal, in response to mechanical endolymphatic flow, was recorded in Frog Ringer's solution and in the presence of different amounts of the various drugs. The degree of ototoxicity was determined by the amount of decrease in the maximal spike account. The degrees of ototoxicity of AGs were calculated to be in the order TOB > GM > ISP > AMK > NTL. This result was in agreement with those of previous morphological investigations. The derivatives of Tum with an R1 branch containing an acidic or a basic amino acid showed greater ototoxicities than those containing aliphatic side chains. The degree of ototoxicity of each drug tended to differ with each concentration, in both AG and Tum derivatives. Thus, the result indicate that chemical structure may be closely related to the degree of ototoxicity.
Assuntos
Antibacterianos/toxicidade , Enviomicina/análogos & derivados , Canais Semicirculares/efeitos dos fármacos , Aminoglicosídeos , Animais , Antibacterianos/química , Enviomicina/química , Enviomicina/toxicidade , Técnicas In Vitro , Rana catesbeianaRESUMO
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.
