Acquired Resistance of Mycobacterium tuberculosis to Bedaquiline

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.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…The demonstration of co-occurrence of canonical mutations in drug target genes and MICs that decrease in the presence of an efflux pump inhibitor, as well as recent studies in clinical isolates, seem to support this new idea. 6,197,198,[199][200][201] Some phylogenetic lineages of M tuberculosis (genotypes) and the strains of these lineages have greater propensity to cause acquired drug resistance-this theory has been especially recognised since the Beijing strain started gaining notoriety in the MDR tuberculosis epidemic. 202 Ford and colleagues 203 did Luria-Delbrück fluctuation analysis on a panel of laboratory and clinical isolates from lineage 2 and lineage 4, to which the Beijing strain belongs, and found the number of mutants per cell plated in a single culture ranged from 2·42 × 10 − ⁹ for the CDC-1551 strain (lineage 2) to 1·94 × 10 − ⁸ for the HN878 strain (lineage 4), which was a significant difference.…”

“…A comprehensive list of these mutations is provided in table 4. 199,222,76,[223][224][225]77 Summary of the rise in drug-resistant tuberculosis New efforts have been made to establish how acquired drug resistance and MDR tuberculosis arise in patients Preclinical studies, prospective clinical studies, and metaanalyses have not identified the role of adherence in acquired drug resistance, contrary to common beliefs. Pharmacokinetic variability has emerged as an important proximate cause of acquired drug resistance in vitro, in mathematical simulations, in prospective clinical studies, and in meta-analyses.…”

“…These resistant mutants show cross-resistance to clofazimine and have been selected for during treatment of patients with pre-XDR and XDR tuberculosis with bedaquiline. 199 In human beings, bedaquiline is highly proteinbound (99·9%), is metabolised by cytochrome P450 isoenzyme 3A (CYP3A) to a less active metabolite (M2), and has a very long terminal half-life (about 5 months). 364 Clearance of the drug is 52% higher in black people, suggesting an undiscovered pharmacogenomic determinant of exposure.…”

Insights into the processes that drive the evolution of drug resistance in Mycobacterium tuberculosis

“…For instance, mutations in the 530 loop and 915 region of rrs gene are associated with streptomycin resistance (Sreevatsan et al., 1996), while mutations in the 1400—1500 region are linked to resistance to kanamycin, amikacin and capreomycin (Jugheli et al., 2009). In particular, cross‐resistance phenomena (Box 1) have also been described in M. tuberculosis (Andries et al., 2014; Jugheli et al., 2009; Vilcheze & Jacobs, 2014). …”

Bedaquiline: 10 years later, the drug susceptibility testing protocol is still pending

“…ANDRIES et al [19] reported that non-target-based resistance to bedaquiline and cross-resistance to clofazimine are due to mutations in Rv0678. Efflux-based resistance was identified in paired isolates from patients treated with bedaquiline as well as in mice, in which it was confirmed to decrease bactericidal efficacy.…”