Scientists at Janssen Pharmaceutica have characterized a novel resistance mechanism to Bedaquiline (BDQ), a second line antibiotic for the treatment of MDR-TB. The research study, published in Plos One, showed that tuberculosis resisted BDQ treatment by developing a mechanism to pump the drug out of the cell. BDQ was recently approved in the European Union for use in patients where established MDR-TB treatments are not effective.
See the author summary below for a description of the research study.
After a long wait of several decades, new drugs are finally reaching patients suffering from drug-resistant tuberculosis (TB). History of TB treatment has shown the importance of understanding mechanism(s) that lead to resistance, so that recommendations for appropriate use can be made and drug susceptibility testing methods can be developed. After describing a target-based mechanism of resistance for bedaquiline, a first in class ATP synthase inhibitor, we now discovered a second mechanism of resistance. Overexpression of the efflux pump MmpS5-MmpL5 leads to resistance to bedaquiline and cross-resistance to clofazimine. Isolates with mutations in the regulator gene of this efflux pump were identified upon exposure to bedaquiline in vitro, in mice and in patients. We confirmed that efflux-based resistance translates into reduced efficacy of bedaquiline in mice and is therefore likely to be clinically relevant. The observed emergence of resistant strains late in the treatment course of mice, and their subsequent elimination by continuation of treatment, underlines the importance of treatment compliance and the risk of premature discontinuation of therapy.
Although the efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of bedaquiline and clofazimine, verapamil failed to increase the bactericidal effect of bedaquiline in mice and was also unable to reverse efflux-based resistance in vivo.