Abstract
Notwithstanding evidence that tuberculosis (TB) is declining, one of the greatest concerns to public health is the emergence and spread of multi-drug resistant strains of Mycobacterium tuberculosis (MDR-TB). MDR-TB are defined as strains which are resistant to at least isoniazid (INH) and rifampicin, the two most potent TB drugs, and their increasing incidence is a serious concern. Recently, notable efforts have been spent on research to pursue novel treatments against MDR-TB, especially on synergistic drug combinations as they have the potential to improve TB treatment. Our research group has previously reported promising synergistic antimicrobial effects between transition-metal compounds and antibiotics in Gram-negative and Gram-positive bacteria. In this work, we evaluated antimycobacterial activity of transition-metals/antibiotics combinatorial treatments against first-line drug resistant strains of Mycobacterium tuberculosis. Our data showed that INH/AgNO3 combinatorial treatment had an additive effect (bactericidal activity) in an isoniazid-resistant clinical strain of Mycobacterium tuberculosis. Moreover, in vitro evaluation of cytotoxicity induced by both, the individual tratments of AgNO3 and INH and the combinatorial treatment of INH/AgNO3 in murine RAW 264.7 macrophages and human A549 lung cells; showed no toxic effects. Together, this data suggests that the INH/AgNO3 combinatorial treatment could be used in the development of new strategies to treat resistant strains of Mycobacterium tuberculosis.
Highlights
Mycobacterium tuberculosis (M. tuberculosis) causes tuberculosis (TB), which is the leading cause of death by infectious diseases worldwide, with an estimated 10.4 million new TB cases in 20161
Ziehl Neelsen stain showed that all the strains were acid-alcohol-resistant bacilli and they presented slow growth, ability to produce niacin and nitrate reduction, which confirmed they were M. tuberculosis strains[18]
Since the MTT assay is an assay for assessing cell metabolic activity, this would explain the observed increase in RAW 264.7 cells. These results suggest that INH, AgNO3 and combinatorial treatment have no toxic effect on A549 lung epithelial cells and RAW 264.7 macrophage cells
Summary
Mycobacterium tuberculosis (M. tuberculosis) causes tuberculosis (TB), which is the leading cause of death by infectious diseases worldwide, with an estimated 10.4 million new TB cases in 20161. The research of new treatments for drug-resistant tuberculosis should be based on novel mechanisms of action relative to the current TB therapy, considering the least amount of undesirable interactions between drugs and the least possible number of side effects; this will lead to obtaining a treatment with a high therapeutic potential in patients with MDR-TB2. Recent literature has reported on the antimycobacterial activity of transition-metals (ions, salts or complexes) in combination with antibiotics. They have reported interesting advances on the antimycobacterial effects of organic compounds; and antibiotics[13,14,15,16] in M. tuberculosis strain H37Rv, which is the most commonly used control for M. tuberculosis identification in the clinical and research laboratory setting, and drug-resistant clinical isolates of M. tuberculosis. We tested the antimycobacterial activity of transition-metals (CuSO4, AgNO3, ZnSO4, and NiSO4) in combination with antibiotics against first-line anti-tuberculosis drug resistant isolates
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