A small molecule increases mycobacterial translation fidelity without a fitness cost by targeting ribosomal protein S5.

A small molecule targeting ribosomal protein S5 enhances mycobacterial translational fidelity without slowing protein synthesis, countering antibiotic tolerance.

• Why it matters: Understanding how to increase translational accuracy without compromising bacterial fitness addresses a critical gap in developing effective antibiotics against tolerant bacteria like Mycobacterium tuberculosis.
• What they did: Researchers screened 9,000 compounds, identified benzo[d]isoxazole-4,7-diones, and optimized a lead compound, 9787, which reduces mistranslation by targeting ribosomal protein S5, without affecting overall translation rates.
• The result: This discovery demonstrates that fidelity can be improved independently of translation speed, offering a novel approach to combat antibiotic tolerance without fitness costs, and reveals the ribosomal small subunit as a druggable target.