Characterisation of Bedaquiline Resistance-Associated Mutations in Drug-Resistant Tuberculosis Phenotypes

Abstract Background In Eswatini, the prevalence of bedaquiline resistance is at an alarming rate of 36%, and notably, there is no study done to profile mutations associated with bedaquiline resistance in Eswatini. Methods Sixty participants were prospectively enrolled from TB clinics based on predefined inclusion criteria. Demographic data were extracted from Medical files. DNA was then extracted using the CTAB method from M. tuberculosis subcultures. The extracted DNA was run on culture-based whole-genome sequencing (WGS), and our data were analysed using TB-profiler. Statistical analyses were conducted using Statistical Package for the Social Sciences version 25 software. Results The Rv0678_p.Met146Thr (n = 16) was the predominant mutation in the mutations associated with the BDQ resistance category. However, most strains harboured the Rv1979c_c.-129A > G (n = 50) and Rv0676c_p.IIe948Val (n = 55), which are mutations associated with bedaquiline resistance-interim. The Rv0678_p.Met146Thr (p = 0.011), Rv1979c_c.129A > G (p = 0.016), Rv0676c_p.Ile948Val (p = 0.016), Rv3245c_p.Met517Leu (p = 0.035), and particularly Rv0676c_c.1065G_T (p = < 0.001) were significantly associated with different TB first-line DR-TB phenotypes. In contrast, Rv0676c_p.Thr794Ile did not show a statistically significant association with first-line drug resistance status. The HR-TB; n = 15/60;25%, possessed pre-existing Rv0678 / mmpR5 mutations. The Rv0678_p.Met146Thr was the only mutation significantly associated with phenotypic BDQ resistance in this cohort. Conclusion The findings indicate that some mutation-related BDQ resistance was significantly associated with different DR-TB phenotypes, suggesting that these mutations may play important roles in the development or maintenance of first-line TB drug resistance. The pre-existing Rv0678 / mmpR5 mutations should be monitored.