Encoded metabolic remodeling amplifies drug resistance in Mycobacterium tuberculosis.

In clinical Lineage 4 strains of Mycobacterium tuberculosis, diversifying selection in idsA2 is linked to acquisition of first-line antibiotic resistance, with engineered variants increasing ethambutol inhibition by two-fold.

• Why it matters: Antibiotic pressure can select mutations that act as steppingstones or enhancers of resistance beyond classic target changes, but the metabolic genes and mechanisms involved are unclear.
• What they did: The study identified idsA2 diversifying selection in Lineage 4 clinical strains and engineered isogenic M. tuberculosis to express clinically prevalent idsA2 variants, then measured drug inhibitory concentrations and performed targeted lipid analyses.
• The result: idsA2 variants altered first-line drug inhibitory concentrations most strongly for ethambutol (two-fold) and redirected isoprenoid synthesis toward increased decaprenyl phosphate species, suggesting an ethambutol resistance mechanism shared with ubiA mutations.

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