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 uptake of sulfonamides and phenolsulfonphthalein (PSP) was examined in vitro using isolated renal proximal tubule suspension, and the effects of nephrotoxic compounds on the uptake of sulfamethizole (SMZ) were studied. The uptake of SMZ and PSP was energy dependent and was inhibited competitively by iodopyracet (IP), which is transported actively by the p-aminohippurate mechanism. The uptake of sulfamethoxazole was also reduced by IP but that of sulfanilamide was negligible. The present results correspond well with those of in vitro experiments reported previously. Nephrotoxic compounds, mercuric chloride, neomycin, viomycin and kanamycin, decreased the uptake of SMZ non-competitively. The inhibitory action of the three antibiotics corresponds with in vivo potency, suggesting that this renal tubule preparation may provide a simple method for predicting the nephrotoxicity of drugs.
Assuntos
Túbulos Renais/metabolismo , Rim/efeitos dos fármacos , Animais , Transporte Biológico/efeitos dos fármacos , Técnicas In Vitro , Canamicina/toxicidade , Masculino , Cloreto de Mercúrio , Mercúrio/toxicidade , Neomicina/toxicidade , Fenolsulfonaftaleína/metabolismo , Coelhos , Sulfametizol/metabolismo , Viomicina/toxicidade , Ácido p-Aminoipúrico/metabolismoRESUMO
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.
