Abstract
Prolonged chemotherapy as well as rapid development of antimicrobial resistance are two of the major concerns for treatment of mycobacterial infections. To enhance the effectiveness of current drug regimens, search for compounds having synergistic interaction with anti-mycobacterial drugs has become indispensable. Here, we have investigated the intervention by oxidative stress, a major factor in mycobacterial pathogenesis, in combination with rifampicin (RIF), a first-line drug used against Mycobacterium tuberculosis. We have observed that a sub-inhibitory concentration of cumene hydroperoxide (CHP), a hydrophobic oxidant, synergistically reduced the minimum inhibitory concentration of RIF by fourfold, with a Fractional Inhibitory Concentration Index (FICI) of 0.45. Also, this interaction was found to be robust and synergistic against different strains of M. smegmatis as well as on M. bovis BCG, with FICI ranging from 0.3 to 0.6. Various physiological, biochemical and molecular parameters were explored to understand the mechanism of synergy. It was observed that increased membrane permeability owing to the presence of the oxidant, led to higher uptake of the drug. Moreover, downregulation of the hydroperoxide reductases by RIF, a transcriptional inhibitor, prevented quenching of the reactive oxygen species produced in the presence of CHP. The lipid soluble reactive species triggered autocatalytic lipid peroxidation (LPO), observed here as extensive membrane damage eventually leading to growth inhibition. Furthermore, it was seen that in combination with hydrogen peroxide (H2O2), the effect was only additive, establishing LPO as a key aspect leading toward synergism. To conclude, this work suggests that targeting the bacterial membrane by a radical species can have a significant impact on the treatment of tuberculosis.
Highlights
Mycobacterial infections are responsible for millions of death worldwide every year, second only to the deaths caused by HIV (WHO, 2016)
The Minimum inhibitory concentration (MIC) of RIF could be decreased by many folds in combination with cumene hydroperoxide (CHP)
Our study presents a novel concept of proposing lipid peroxidation (LPO) causing oxidative agents, such as CHP, as adjuvants to the current regime of tuberculosis
Summary
Mycobacterial infections are responsible for millions of death worldwide every year, second only to the deaths caused by HIV (WHO, 2016). With dwindling discovery of new drugs, combination therapy with existing non-tuberculosis drugs is being explored as an alternative strategy to identify novel drug pairs that have a synergistic effect on the bacteria (Rey-Jurado et al, 2013; Bruhn et al, 2015; Gonzaloa et al, 2015; Zhang et al, 2015; Zou et al, 2015). Both the molecules in a combination do not need to have an antimicrobial effect. Citric-acid coated nanoparticles increased the permeability of cells making them more sensitive to rifampicin (Padwal et al, 2015)
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