RESUMEN
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.
Asunto(s)
Girasa de ADN/química , Naftoquinonas/química , Adenosina Trifosfato/química , Antiinfecciosos/farmacología , Sitios de Unión , Dominio Catalítico , ADN/genética , Girasa de ADN/metabolismo , Escherichia coli/metabolismo , Humanos , Concentración 50 Inhibidora , Espectrometría de Masas/métodos , Modelos Químicos , Mycobacterium tuberculosis/metabolismo , Unión Proteica , Estructura Terciaria de Proteína , Staphylococcus aureus/metabolismo , Resonancia por Plasmón de Superficie , Tuberculosis/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Antineoplásicos Fitogénicos , Antituberculosos , Diterpenos , Orthosiphon/química , Plantas Medicinales/química , Salvia/química , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Antituberculosos/química , Antituberculosos/aislamiento & purificación , Antituberculosos/farmacología , Diterpenos/química , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Mycobacterium tuberculosis/efectos de los fármacosRESUMEN
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.