P13

Whole genome sequencing has the potential to detect resistance mutations associated with new and repurposed drugs (NRD) and to guide treatment of MDR-TB. However, the knowledge base to confidently interpret mutations associated with resistance to NRD is sparse. In this study, we screened 900 M. tuberculosis complex genomes from Ireland, a low TB incidence country, for all mutations in 13 candidate genes and promoter regions associated with resistance to BDQ, CFZ, DLM and LZD. We identified a large diversity of mutations in BDQ/CFZ (n=59), DLM (n=74) and LZD (n=2) candidate genes occurring in 195 clinical isolates potentially associated with resistance. Notably, these mutations were identified mostly among drug susceptible TB isolates. Phenotypic DST in the BACTEC MGIT 960 system was performed on selected isolates to assess their association with resistance. We identified BDQ resistance among two drug susceptible isolates which harboured mutations in Rv0678 and mmpL5. Importantly, BDQ resistance was also identified in two MDR-TB isolates which dated back to 2007, prior to the introduction of BDQ. Two isolates with loss of function mutations in mmpL5 were associated with BDQ/CFZ susceptible phenotypes. High level DLM resistance was observed in two drug susceptible isolates with frameshift mutations in ddn. No mutations were related to linezolid resistance. Overall, our results suggest the circulation of M. tuberculosis with resistance to BDQ and DLM which is not being detected as part of routine phenotypic DST; a cause for concern. In addition, this work will contribute to the development of future WHO mutation catalogues.