RESUMO
Aim: To evaluate the modulatory effect of piperine (PIP) on streptomycin (SM) activity in Mycobacterium tuberculosis (Mtb). Materials & methods: SM and PIP minimum inhibitory concentration (MIC) and combinatory activity were determined in Mtb H37Rv and in susceptible and resistant clinical isolates. Ethidium bromide accumulation assay and relative quantification of efflux pumps genes (rv1258c, rv1218c and rv2942), after SM and SM+PIP combination exposure, were also performed. Results: PIP concentration of 25 µg/ml (1/4× MIC) was able to inhibit efflux pumps activity, to modulate SM activity in Mtb, and conducted changes in the relative quantification of efflux pumps genes. Conclusion: SM+PIP combination was able to rescue the SM-susceptible MIC values in SM-resistant Mtb.
Assuntos
Alcaloides/farmacologia , Antituberculosos/farmacologia , Benzodioxóis/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/farmacologia , Alcamidas Poli-Insaturadas/farmacologia , Estreptomicina/farmacologia , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Sinergismo Farmacológico , Humanos , Proteínas de Membrana Transportadoras/genética , Proteínas de Membrana Transportadoras/metabolismo , Testes de Sensibilidade MicrobianaRESUMO
Aim: To evaluate an assay to detect minimum bactericidal concentration (MBC) in Mycobacterium tuberculosis, using as single model rifampicin, isoniazid, levofloxacin (LVX) and linezolid (LNZ) and in combination. Material & methods: MBCs were carried out directly from resazurin microtiter assay plate and 3D checkerboard in M. tuberculosis H37Rv and five resistant clinical isolates. Results: The proposed MBC assay showed similar values to those determined by MGIT™, used as control. LVX and LNZ's MBC values were close to their MIC values. LNZ or LVX combined with isoniazid and rifampicin showed MBC value reduced in 63.7% of the assays. Conclusion: The proposed assay to determine MBCs of drugs can be applied to the study of new compounds with anti-M. tuberculosis activity to detect their bactericidal effect and also in laboratory routine for clinical dose adjustment of drugs according to the patient's profile.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Tuberculose/tratamento farmacológico , Farmacorresistência Bacteriana Múltipla , Sinergismo Farmacológico , Humanos , Isoniazida/farmacologia , Levofloxacino/farmacologia , Linezolida/farmacologia , Testes de Sensibilidade Microbiana , Rifampina/farmacologiaRESUMO
Aim: To evaluate the potential of three benzohydrazones (1-3), four acylhydrazones derived from isoniazid (INH-acylhydrazones) (4-7) and one hydrazone (8) as antituberculosis agents. Materials & methods: Inhibitory and bactericidal activities were determined for the reference Mycobacterium tuberculosis (Mtb) strain and clinical isolates. Cytotoxicity, drug combinations and ethidium bromide accumulation assays were also performed. Results: The tested compounds (1-8) presented excellent antituberculosis activity with surprisingly inhibitory (0.12-250 µg/ml) and bactericidal values, even against multidrug-resistant Mtb clinical isolates. Compounds showed high selectivity index, with values reaching 1833.33, and a limited spectrum of activity. Some of the compounds (2 & 8) are also great inhibitors of bacillus efflux pumps. Conclusion: Benzohydrazones and INH-acylhydrazones may be considered scaffolds for the development of new anti-Mtb drugs.
Assuntos
Antituberculosos/farmacologia , Hidrazonas/farmacologia , Isoniazida/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Animais , Antituberculosos/síntese química , Antituberculosos/química , Linhagem Celular Tumoral , Chlorocebus aethiops , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Etídio/metabolismo , Células HeLa , Humanos , Hidrazonas/síntese química , Hidrazonas/química , Isoniazida/síntese química , Isoniazida/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mycobacterium tuberculosis/isolamento & purificação , Tuberculose/microbiologia , Células VeroRESUMO
AIM: To evaluate (i) the in vitro activity of eugenol (EUG) and three derivatives against Mycobacterium tuberculosis (Mtb), nontuberculous mycobacteria (NTM) and other bacteria, (ii) the EUG and antituberculosis drugs combinatory effect and (iii) the EUG and its derivatives cytotoxicity. MATERIALS & METHODS: Minimum inhibitory concentration of the compounds were determined by resazurin microtiter or broth microdilution assay and the drug interaction between EUG and antituberculosis drugs by resazurin drug combination microtiter. The cytotoxicity was carried out in macrophages, HeLa and VERO cells. Results: EUG and derivatives displayed activity and synergic effect of EUG combined with rifampicin, isoniazid, ethambutol, and pyrazinamide in Mtb including multidrug-resistant isolates, with more selectivity to bacillus than macrophages, HeLa and VERO cells (selective index from 0.65 to 31.4). EUG derivatives (4-allyl-2-methoxyphenyl acetate, 4-allyl-2-methoxyphenyl benzoate, and 4-allyl-2-methoxyphenyl 4-nitrobenzoate) were more active against nontuberculous mycobacteria than EUG. EUG and derivatives exhibited low activity in other Gram-positive and -negative bacteria. CONCLUSION: EUG and its derivatives show activity against Mycobacterium spp. and synergic effect of EUG combined with antituberculosis drugs against Mtb.
