Profiling of BDQ-induced transcriptome suggests amino acid metabolism and stress responses as alternate mechanisms contributing to BDQ tolerance in.

UNLABELLED: Under bedaquiline (BDQ) pressure, a temporary persistence period (24-96 h) has been observed, during which H37Rv undergoes metabolic rerouting. However, little is known of transcriptomic changes in BDQ-resistant(Mtb) isolates during this period. We explored transcriptomic adaptations occurring under inhibitory concentrations of BDQ to delineate pathways supporting drug tolerance and contributing to BDQ resistance. We report overexpression of genes involved in the biosynthesis of L-arginine and L-cysteine in our study isolates. Among stress response genes, genes from theoperon, involved in Fe-S biogenesis, were upregulated in the study isolates. Differentially expressed amino acid gene clusters likely indicate an under-recognized metabolic pathway contributing to BDQ persistence in the study clinical isolates. Furthermore, Fe-S stress response activated under BDQ pressure may be of particular interest as a mechanism broadly used by Mtb in mitigating different environmental stresses. We propose that these pathways should be explored further as potential drug targets.

IMPORTANCE: Keeping in mind the complex interplay between mutations, gene expression, and drug resistance, knowledge of pathways induced under bedaquiline (BDQ) stress in BDQ-resistant clinical(Mtb) isolates is limited. Furthermore, focusing on mechanisms supporting tolerance can help identify potential targets for drugs that act against dormant bacilli or select synergistic drug combinations. Such information may be useful in identifying other alternate mechanisms of resistance and tolerance. Our study explores changes occurring in the transcriptome of BDQ-resistant isolates exposed to inhibitory concentrations of BDQ under a specific tolerance time point. Our study identifies differentially expressed pathways and genes that are: (i) similarly expressed in both H37Rv strain and clinical isolates, (ii) expressed only in clinical isolates, and (iii) reported to be similarly induced by literature in Mtb exposed to other anti-tuberculosis drugs. These genes and pathways present themselves as potential markers that may have diagnostic, prognostic, and therapeutic value that can be explored further.