| Summary: | Abstract Mutations in whiB7 have been associated with both hypersusceptibility and resistance to various antibiotics in Mycobacterium tuberculosis (Mtb). Unlocking the secrets of antibiotic resistance in the bacterium, we examined mutations in the coding sequences of whiB7 of over 40,000 diverse Mtb isolates. Our results unveil the dominant c.191delG (Gly64delG) mutation, present in all members of the lineage L1.2.2 and its impact on WhiB7's conserved GVWGG-motif, causing conformational changes and deletion of the C-terminal AT-hook. Excitingly, we discovered six unique mutations associated with partial or total deletion of the AT-hook, specific to certain sublineages. Our findings suggest the selective pressures driving these mutations, underlining the potential of genomics to advance our understanding of Mtb's antibiotic resistance. As tuberculosis remains a global health threat, our study offers valuable insights into the diverse nature and functional consequences of whiB7 mutations, paving the way for the development of novel therapeutic interventions.
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