Transcriptional profiling of a laboratory and clinical Mycobacterium tuberculosis strain in the presence of the drug Delamanid

In this study, the transcriptional response of two Mycobacterium tuberculosis strains to a pressure of the recently approved delamanid is investigated. RNA sequencing revealed that the response to this bicyclic nitroimidazole shows many similarities with the anti-tuberculous drug from the same class pretomanid. Although delamanid is found to inhibit cell wall synthesis, the expression of genes involved in this process were only mildly affected. In contrast, a clear parallel was found with components that affect aerobic respiration. This demonstrates that respiratory poisoning plays a fundamental role in the bactericidal effect of delamanid. Remarkably, the most highly induced genes comprise poorly characterized genes for which functional characterization might hint to the target molecule(s) of delamanid and its exact mode of action. Overall design: To investigate the transcriptional response of MTB to exposure of delamanid, triplicates of a laboratory (H37Rv) and a DLM susceptible clinical (ITM-04-1195) MTB strain were spiked with a bactericidal concentration of delamanid or its solvent DMSO, and sampled after 6h and 24h of incubation. Total RNA was extracted, RNA sequencing and differential expression analyses were performed.