Enhance the Antimycobacterial Activity of Streptomycin with Ebselen as an Antibiotic Adjuvant Through Disrupting Redox Homeostasis.

PURPOSE

Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against () which is genetically related to () and resistant to many antituberculosis drugs.

METHODS

Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model.

RESULTS

The results reveal that EbSe acts as an antibiotic adjuvant over SM on . EbSe + SM disrupted the intracellular redox microenvironment of by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity.

CONCLUSION

The above studies suggest that EbSe significantly enhanced the anti- effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.