Mutations in <i>Rv0678</i> Reduce Susceptibility of Mycobacterium tuberculosis to the DprE1 Inhibitor TBA-7371

We read with interest the article by Poulton et al. (1) demonstrating that mutations in the Rv0678 gene confer low-level resistance to benzothiazinone inhibitors of decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) in Mycobacterium tuberculosis. DprE1 is an essential enzyme for arabinogalactan synthesis to form the M. tuberculosis cell wall (2). It is the target of four new antituberculosis drugs that are currently in clinical development, namely, BTZ043, PBTZ169, TBA-7371, and OPC-167832 (3). Reports now implicate mutations in Rv0678, which encodes a transcriptional repressor of the MmpS5-MmpL5 transporter, in resistance to three of these DprE1 inhibitors (i.e., OPC-167832, BTZ043, and PBTZ169) (1, 4). The fourth DprE1 inhibitor, TBA-7371, is structurally distinct (5) and, to our knowledge, no reports of the impact of Rv0678 mutations on susceptibility to TBA-7371 exist. Therefore, we tested the TBA-7371 susceptibility of two isogenic Rv0678 mutants that were previously selected from wild-type M. tuberculosis H37Rv by bedaquiline and were confirmed to have reduced bedaquiline susceptibility. One mutant has an IS6110 insertion in Rv0678 (POI: aa16/nt49), disrupting the gene (6), whereas the second mutant has a +A insertion at nt274-275 and has been reported in clinical isolates with bedaquiline resistance (6, 7).