Analysis of drug-resistance to bedaquiline and relationships between phenotypes and genotypes in multidrug-resistant Mycobacterium tuberculosis strains

Abstract

Objective To evaluate the resistance of multidrug-resistant Mycobacterium tuberculosis (M.tb) strains to bedaquiline (BDQ) and to analyze the relationships between their genotypes and BDQ-resistant phenotypes in order to provide a scientific basis for rational use of BDQ for the treatment of multidrug-resistant tuberculosis (MDR-TB) in clinical practice. Methods A total of 387 clinical M. tb strains, including 100 pan-susceptible strains and 287 strains isolated from patients with MDR (MDR-TB strains), were enrolled in this study. Of the 287 MDR-TB strains, 77 strains were collected in Chongqing in 2015 and the other strains were collected in a national drug-resistant tuberculosis survey conducted in China during 2007 to 2008. Minimum inhibitory concentrations (MIC) of BDQ against those strains were detected. Genotypes of those strains were analyzed by Spoligotyping. Differences in the resistant rates against BDQ between Beijing genotype and non-Beijng genotype MDR-TB strains were comparatively analyzed. Results MIC50 and MIC90 of BDQ against the 287 MDR-TB strains were 0.03 μg/ml and 0.25 μg/ml, respectively. Nineteen out of the 287 MDR-TB strains (6.6%) were resistant to BDQ. Based on the Spoligotyping, 195 strains were classified into Beijing genotype, and the other 92 strains belonged to non-Beijing genotype. Statistical analysis revealed that the BDQ-resistant rate in Being genotype strains (4.6%, 9/195) was lower than that in non-Beijing genotype strains (10.9%, 10/92, χ2=3.955, P=0.047). In addition, the MIC50 and MIC90 of BDQ against pan-susceptible strains were 0.03 μg/ml and 0.12 μg/ml, respectively. Sixty-three pan-susceptible strains belonged to Beijing genotype and the other 37 strains belonged to non-Beijing genotype. None of the pan-susceptible strains was resistant to BDQ. Conclusion This study indicates that BDQ showed stronger in vitro antibacterial activity against the MDR-TB strains isolated in China. A correlation between non-Beijing genotype and BDQ resistance is observed in those MDR strains. MDR strains of Beijing genotype are more susceptible to BDQ than those of non-Beijing genotype. Key words: Mycobacterium tuberculosis; Multidrug resistance; Drug susceptibility; Bedaquiline; Genotype