P06

High-confidence resistance mutations for new and repurposed anti-TB drugs are rare and more data is needed in order to correctly interpret the results generated by genotypic drug susceptibility testing. Several genes have been reported to be implicated in resistance to delamanid (DLM) and pretomanid (Pa), among them ddn, which encodes a deazaflavin-dependent nitroreductase responsible for the activation of both DLM and Pa. The aim of this study was to evaluate the role of the ddn mutation Trp20Stop in DLM and Pa resistance.

Eleven isolates (nine fully drug-susceptible and two mono-isoniazid resistant) harboring ddn_Trp20Stop were identified in the Swedish national Mycobacterium tuberculosis strain collection. All isolates had been assigned to lineage 4.5 and were tested for DLM and Pa resistance in the BACTEC MGIT 960 system together with 13 consecutive lineage 4.5 isolates lacking ddn_Trp20Stop as a control group. All isolates carrying ddn_Trp20Stop were resistant to 0.06 mg/L DLM and 1.0 mg/L Pa. Conversely, the 13 lineage 4.5 isolates without ddn_Trp20Stop were all susceptible to the two drugs.

The results indicate that the ddn mutation Trp20Stop should be classified as a high-confidence marker for DLM and Pa resistance. Its confinement to susceptible, or at most isoniazid-monoresistant, lineage 4.5 isolates suggests that a sublineage or branch within lineage 4.5 is intrinsically resistant to DLM and Pa.