Spontaneous mutations to delamanid and pretomanid resistance in Mycobacterium tuberculosis: SNPs confer high-level resistance - PubMed
3 hours ago
- #mutations
- #drug-resistance
- #tuberculosis
- Multidrug-resistant tuberculosis (MDR-TB) is a significant global health concern.
- Delamanid (DLM) and pretomanid (PMD) are key drugs in MDR-TB treatment regimens, but resistance mutations are not well understood.
- In vitro experiments selected for resistance to DLM or PMD using Mycobacterium tuberculosis H37Rv cultures.
- Resistant clones were selected at twice the critical concentrations of DLM (0.4 μg/mL) or PMD (4 μg/mL).
- Whole-genome sequencing (WGS) identified 102 mutations across six resistance-associated genes (ddn, fgd1, fbiA, fbiB, fbiC, fbiD).
- Most isolates showed high-level cross-resistance to both DLM and PMD (MIC ≥ 32 × CC).
- Non-synonymous SNPs, loss-of-function mutations, and inframe indels were found to confer high-level resistance.
- Only six of the 111 identified mutations had been reported in previous in vitro studies.
- 14 loss-of-function mutations were classified as resistant according to the WHO mutation catalogue.
- The study highlights a high diversity of resistance mutations, with most conferring resistance to both DLM and PMD.