Abstract
Bedaquiline (BDQ), an ATP synthase inhibitor, is the first drug to be approved for treatment of multi-drug resistant tuberculosis in decades. In vitro resistance to BDQ was previously shown to be due to target-based mutations. Here we report that non-target based resistance to BDQ, and cross-resistance to clofazimine (CFZ), is due to mutations in Rv0678, a transcriptional repressor of the genes encoding the MmpS5-MmpL5 efflux pump. Efflux-based resistance was identified in paired isolates from patients treated with BDQ, as well as in mice, in which it was confirmed to decrease bactericidal efficacy. The efflux inhibitors verapamil and reserpine decreased the minimum inhibitory concentrations of BDQ and CFZ in vitro, but verapamil failed to increase the bactericidal effect of BDQ in mice and was unable to reverse efflux-based resistance in vivo. Cross-resistance between BDQ and CFZ may have important clinical implications.
Highlights
BDQ (Sirturo, TMC207) was recently granted accelerated approval as part of combination therapy to treat adults with multidrug resistant pulmonary tuberculosis (TB) when an effective treatment regimen cannot otherwise be provided [1]
After identifying the efflux system MmpS5-MmpL5 as being responsible for non-target based resistance, we studied the effect of efflux pump inhibitors (EPIs) on BDQ’s in vitro minimal inhibitory concentrations (MICs) and in vivo efficacy in mice
In non-atpE mutant strain EH 3.2, a non-synonymous single nucleotide polymorphism was observed in Rv0678 gene (A202G leading to S68G), while in strain EH 3.6, a non-synonymous single nucleotide polymorphism was observed in ppsC gene (G5408T leading to G1803V)
Summary
BDQ (Sirturo, TMC207) was recently granted accelerated approval as part of combination therapy to treat adults with multidrug resistant pulmonary tuberculosis (TB) when an effective treatment regimen cannot otherwise be provided [1]. Inhibition of ATP synthase, was discovered through whole genome sequencing of resistant mutants that were selected in vitro [2]. We selected Mycobacterium tuberculosis isolates with increased minimal inhibitory concentrations (MICs) for BDQ in vitro, in mice and in patients, and studied these for non-target based mechanisms of resistance. After identifying the efflux system MmpS5-MmpL5 as being responsible for non-target based resistance, we studied the effect of efflux pump inhibitors (EPIs) on BDQ’s in vitro MICs and in vivo efficacy in mice. Hartkoorn et al recently described the in vitro isolation of CFZ-resistant strains, with cross-resistance to BDQ, by up-regulation of the MmpS5MmpL5 efflux system [5] Both CFZ and BDQ can select for efflux-based resistance, leading to cross-resistance between the two drugs
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