RESUMO
Tuberculosis and other bacterial diseases represent a significant threat to human health. The DNA topoisomerases are excellent targets for chemotherapy, and DNA gyrase in particular is a well-validated target for antibacterial agents. Naphthoquinones (e.g. diospyrin and 7-methyljuglone) have been shown to have therapeutic potential, particularly against Mycobacterium tuberculosis. We have found that these compounds are inhibitors of the supercoiling reaction catalyzed by M. tuberculosis gyrase and other gyrases. Our evidence strongly suggests that the compounds bind to the N-terminal domain of GyrB, which contains the ATPase active site, but are not competitive inhibitors of the ATPase reaction. We propose that naphthoquinones bind to GyrB at a novel site close to the ATPase site. This novel mode of action could be exploited to develop new antibacterial agents.
Assuntos
DNA Girase/química , Naftoquinonas/química , Trifosfato de Adenosina/química , Anti-Infecciosos/farmacologia , Sítios de Ligação , Domínio Catalítico , DNA/genética , DNA Girase/metabolismo , Escherichia coli/metabolismo , Humanos , Concentração Inibidora 50 , Espectrometria de Massas/métodos , Modelos Químicos , Mycobacterium tuberculosis/metabolismo , Ligação Proteica , Estrutura Terciária de Proteína , Staphylococcus aureus/metabolismo , Ressonância de Plasmônio de Superfície , Tuberculose/tratamento farmacológicoRESUMO
The known (+)-trans-ozic acid (1) and two new labdane diterpenoids (2 and 3) have been isolated from an ethanol extract of Orthosiphon labiatus. The structures of 2 and 3 were established mainly by 1D and 2D NMR spectroscopic means. The ethanolic extract of Salvia africana-lutea afforded the known abietane diterpenoids carnosol (4), rosmadial (5), and carnosic acid (characterized as its derivative 6). Compounds 3 and 6 exhibited MICs of 157 and 28 microM, respectively, against Mycobacterium tuberculosis, while 2 and 6 showed cytotoxic activity with IC50 82 and 69 microM, respectively, against a breast (MCF-7) human cancer cell line.
Assuntos
Antineoplásicos Fitogênicos , Antituberculosos , Diterpenos , Orthosiphon/química , Plantas Medicinais/química , Salvia/química , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antituberculosos/química , Antituberculosos/isolamento & purificação , Antituberculosos/farmacologia , Diterpenos/química , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Humanos , Concentração Inibidora 50 , Estrutura Molecular , Mycobacterium tuberculosis/efeitos dos fármacosRESUMO
Phytochemical studies of an ethanolic extract of Euclea natalensis root bark afforded two new compounds, octahydroeuclein (1) and 20(29)-lupene-3 beta-isoferulate (2), in addition to three known compounds, shinanolone (3), lupeol, and betulin. The chemical structures of 1 and 2 were determined by spectroscopic means. Shinanolone (3) showed inhibitory activity against Gram-positive bacterial strains and a drug-sensitive strain of Mycobacterium tuberculosis at a concentration of 0.1 mg/mL.
