RESUMO
The combinatorial chemistry has been an important tool for the development of new strategies against the Mycobacterium tuberculosis. Therefore, we evaluated the antimycobacterial activity of two coordinated metal complexes (Cu(II) and Co(II)) and a free ligand, including in the intramacrophage environment. The complexes were more active than the free ligand, indicating that the complexation favoured the antimicrobial activity. None of the compounds showed cytotoxic effect at the concentration of 200 µg ml-1 and both complexes showed intracellular antimicrobial activity, with results as effective as rifampicin. In this study, it was possible to identify complexes containing benzohydroxamate associated with transition metal ions (Cu2+ and Co2+ ), which were able to inhibit the growth of M. tuberculosis, including in persistence stage. In addition, the docking analysis allows inferring a possible interaction of the metal complexes with the enzyme urease, which has been reported as crucial for the bacillus survival in the intraphagosomal environment. Thus, these set of results demonstrate the potential of these metals in the development of new drugs against M. tuberculosis. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, it was possible to identify complexes containing benzohydroxamate associated with transition metals (Cu2+ and Co2+ ), which were able to inhibit the growth of Mycobacterium tuberculosis, including in the persistence stage. In this context, cobalt and copper can be scaffolds for new drugs against M. tuberculosis.
Assuntos
Antituberculosos/farmacologia , Cobalto/farmacologia , Cobre/farmacologia , Macrófagos/microbiologia , Mycobacterium tuberculosis/efeitos dos fármacos , Antituberculosos/química , Cobalto/química , Cobre/química , Humanos , Ácidos Hidroxâmicos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/crescimento & desenvolvimentoRESUMO
Tuberculosis remains a serious public health problem, worsened by an increased frequency of multidrug-resistant Mycobacterium tuberculosis. We report here a retrospective study of resistance to antituberculosis drugs of 170 strains of M. tuberculosis isolated from the state of Rio Grande do Sul, Brazil. The frequency of resistance to at least one drug was 34%, while 22% were resistant to more than one drug. Among the strains isolated from patients without a history of previous treatment for tuberculosis, patients with positive serology for HIV and patients with previous treatment for tuberculosis, the resistance to at least one drug was 14, 27 and 73%, respectively. Multidrug-resistant tuberculosis, defined as resistant to at least rifampicin (RMP) and isoniazid (INH), was found in the groups of patients without previous treatment, HIV co-infected and with previous treatment for tuberculosis at 10, 17 and 44%, respectively. With the purpose of evaluating whether the sensitivity test to INH and RMP would be a good marker to indicate resistance to other antituberculosis drugs, sensitivity tests were performed with four more drugs in 32 strains, initially classified as resistant to INH, RMP or both. Of 18 strains resistant to INH and RMP simultaneously, 89% showed resistance to four more drugs.