Antibacterial Activity of combinatorial treatments composed of transition-metal/antibiotics against Mycobacterium tuberculosis

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.