RESUMO
The antimycobacterial activities of disulfiram (DSF) and diethyldithiocarbamate (DDC) against multidrug- and extensively drug-resistant tuberculosis (MDR/XDR-TB) clinical isolates were evaluated in vitro. Both DSF and DDC exhibited potent antitubercular activities against 42 clinical isolates of M. tuberculosis, including MDR/XDR-TB strains. Moreover, DSF showed remarkable bactericidal activity ex vivo and in vivo. Therefore, DSF might be a drug repurposed for the treatment of MDR/XDR-TB.
Assuntos
Antituberculosos/farmacologia , Dissulfiram/farmacologia , Ditiocarb/farmacologia , Tuberculose Extensivamente Resistente a Medicamentos/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose/tratamento farmacológico , Animais , Antituberculosos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Tuberculose Extensivamente Resistente a Medicamentos/tratamento farmacológico , Camundongos , Camundongos Endogâmicos ICR , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/microbiologia , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológicoRESUMO
The present study was undertaken to optimize the anti-tubercular activity of 2-acetamido-2-deoxy-ß-D-glucopyranosyl N,N-dimethyldithiocarbamate (OCT313, Glc-NAc-DMDC), a lead compound previously reported by us. Structural modifications of OCT313 included the replacements of the DMDC group at C-1 by pyrrolidine dithiocarbamate (PDTC) and the acetyl group at C-2 by either propyl, butyl, benzyl or oleic acid groups. The antimycobacterial activities of these derivatives were evaluated against Mycobacterium tuberculosis (MTB). Glc-NAc-pyrrolidine dithiocarbamate (OCT313HK, Glc-NAc-PDTC) exhibited the most potent anti-tubercular activity with the minimal inhibitory concentration (MIC) of 6.25-12.5 µg/ml. The antibacterial activity of OCT313HK was highly specific to MTB and Mycobacterium bovis BCG, but not against Mycobacterium avium, Mycobacterium smegmatis, Staphylococcus aureus or Escherichia coli. Importantly, OCT313HK was also effective against MTB clinical isolates, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) strains. Interestingly, OCT313HK was exerted the primary bactericidal activity, and it was also exhibited the bacteriolytic activity at high concentrations. We next investigated whether the mycobacterial monooxygenase EthA, a common activator of thiocarbamide-containing anti-tubercular drugs, also activated OCT313HK. Contrary to our expectations, the anti-tubercular activity of dithiocarbamate sugar derivatives and dithiocarbamates were not dependent on ethA expression, in contrast to thiocarbamide-containing drugs. Overall, this study presents OCT313HK as a novel and potent compound against MTB, particularly promising to overcome drug resistance.
Assuntos
Antituberculosos/síntese química , Carboidratos/química , Tiocarbamatos/química , Tioglucosídeos/síntese química , Antituberculosos/química , Antituberculosos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Mycobacterium tuberculosis/efeitos dos fármacos , Oxirredutases/antagonistas & inibidores , Oxirredutases/metabolismo , Tiocarbamatos/síntese química , Tiocarbamatos/farmacologia , Tioglucosídeos/química , Tioglucosídeos/farmacologiaRESUMO
A series of sugar derivatives (1-13) were synthesized and evaluated for antibacterial activity against Mycobacteriumtuberculosis (MTB), especially multi-drug resistant (MDR) MTB, and the structure-activity relationships of these compounds were studied. The results showed that the compound OCT313 (2-acetamido-2deoxy-beta-D-glucopyranosyl N,N-dimethyldithiocarbamate) (4) exhibited significant in vitro bactericidal activity, and that the dithiocarbamate group at C-1 position of the glucopyranoside ring was requisite for the antibacterial activity.